Dictionary of

Natural Products
on CD-ROM
This introduction screen gives access to (a) a general introduction to the
scope and content of DNP on CD-ROM, followed by (b) an extensive
review of the different types of natural product and the way in which they
are organised and categorised in DNP.
You may access the section of your choice by clicking on the
appropriate line below, or you may scroll through the text forwards or
backwards from any point.

Introduction to the DNP database page 3

Data presentation and organisation 3
Derivatives and variants 3
Chemical names and synonyms 4
CAS Registry Numbers 6
Diagrams 7
Stereochemical conventions 7
Molecular formula and molecular weight 8
Source 9
Importance/use 9
Type of Compound 9
Physical Data 9
Hazard and toxicity information 10
Bibliographic References 11
Journal abbreviations 12
Entry under review 12

Description of Natural Product Structures 13

Aliphatic natural products 15
Semiochemicals 15
Lipids 22

Polyketides 29

Carbohydrates 35

Oxygen heterocycles 44

Simple aromatic natural products 45

Benzofuranoids 48

Benzopyranoids 49

1
Flavonoids page 51

Tannins 60

Lignans 64

Polycyclic aromatic natural products 68

Terpenoids 72
Monoterpenoids 73
Sesquiterpenoids 77
Diterpenoids 101
Sesterterpenoids 118
Triterpenoids 121
Tetraterpenoids 131
Miscellaneous terpenoids 133
Meroterpenoids 133

Steroids 135
The sterols 140

Aminoacids and peptides 148

Aminoacids 148
Peptides 150
β-Lactams 151
Glycopeptides 153

Alkaloids 154
Alkaloids derived from ornithine 154
Alkaloids derived from lysine 156
Alkaloids derived from nicotinic acid 158
Alkaloids of polyketide origin 159
Alkaloids derived from anthranilic acid 160
Alkaloids derived wholly or in part from phenylalanine or
tyrosine 163
Isoquinoline alkaloids 163
Alkaloids derived from tryptophan 181
Monoterpenoid indole alkaloids 184
Terpenoid alkaloids 196
Steroidal alkaloids 200
Imidazole alkaloids 202
Oxazole alkaloids 202
Thiazole alkaloids 203
Pyrazine and quinoxaline alkaloids 203
Pyrrole alkaloids 203
Putrescine alkaloids 203
Spermine and spermidine alkaloids 203
Peptide alkaloids 204
Purines 205
Pteridines and analogues 205

Polypyrroles 206

2
Introduction to the DNP database
The Chapman & Hall/CRC Chemical Database is a structured database holding
information on chemical substances. It includes descriptive and numerical data
on chemical, physical and biological properties of compounds; systematic and
common names of compounds; literature references; structure diagrams and
their associated connection tables. The Dictionary of Natural Products on
CD-ROM is a subset of this database and includes all compounds contained in
the Dictionary of Natural Products (Main Work and Supplements).
The Dictionary of Natural Products (DNP) is the only comprehensive and
fully-edited database on natural products. It arose as a daughter product of the
well-known Dictionary of Organic Compounds (DOC) which, since its
inception in the 1930s has, through successive editions, always been a leading
source of natural product information.
In the early 1980s, following the publication of the Fifth Edition of DOC, the
first to be founded on database methods, the Editors and contributors for the
various classes of natural products embarked on a programme of enlargement,
rationalisation and classification of the natural product entries, while at the same
time keeping the coverage up-to-date. In 1992 the results of this major project,
which had grown to match DOC in size, were separately published in both book
(7 volumes) and CD-ROM format, leaving DOC with coverage of only the most
widely distributed and/or practically important natural products. DNP compi-
lation has since continued unabated by a combination of an exhaustive survey of
current literature and of historical sources such as reviews to pick up minor
natural products and items of data previously overlooked.
The compilation of DNP is undertaken by a team of academics and
freelancers who work closely with the in-house editorial staff at Chapman &
Hall. Each contributor specialises in a particular natural product class (e.g.
alkaloids) and is able to reorganise and classify the data in the light of new
research so as to present it in the most consistent and logical manner possible.
Thus the compilation team is able to reconcile errors and inconsistencies.
The resulting CD-ROM version, which is re-issued every six months,
represents an extremely well organised dictionary documenting virtually every
known natural product.
A valuable feature of the design is that closely related natural products (e.g.
where one is a glycoside or simple ester of another) are organised into the same
entry, thus simplifying and bringing out the underlying structural and
biosynthetic relationships of the compounds. Structure diagrams are drawn and
numbered in the most consistent way according to best stereochemical and
biogenetic relationships. In addition, every natural product is indexed by
structural/biogenetic type under one of more than 1000 headings, allowing the
rapid location of all compounds in the category, even where they have under-
gone biogenetic modification and no longer share exactly the same skeleton.
There is extensive (but not complete) coverage of natural products of
unknown structure, and the coverage of these is currently being enhanced by
various retrospective searches.

Data presentation and organisation

Derivatives and variants
In the database, closely related compounds are grouped together to form an
entry. Stereoisomers and derivatives of a parent compound are all listed under
one entry. The compounds in the Dictionary of Natural Products are grouped

3
together into approximately 40,000 entries. The structure of an entry is shown
below.

Entry (parent compound)

Derivatives
Variants (stereoisomers or other
closely-related compounds)
Derivatives of the variant

A simple entry covers one compound, with no derivatives or variants. A

composite entry will start with the entry compound, then may have:
one or more derivatives at entry level
one or more variants of the entry
one or more derivatives of the variant.
Variants may include stereoisomers, e.g. (R)-form, endo-form; members of a
series of natural products with closely related structures such as antibiotic
complexes.
For example, Trienomycins are often treated as variants although their
structures may be more varied.
Derivatives may include hydrates, complexes, salts, classical organic deriv-
atives, substitution products and oxidation products etc. Derivatives may exist
on more than one functional group of an entry compound.
The following techniques are among those used to bring together related
substances in the same entry:
(a) Glycosides are given as derivatives of the parent aglycone, except for
those glycosides which have an extensive literature in their own right (e.g.,
Digoxin)
(b) Acyl derivatives are extremely common and are listed under the parent
compound, again unless it has as extensive literature of its own
(c) N-Alkyl and O-Alkyl derivatives such as methyl ethers of phenols are
similarly given under the parent compound.

Data Types
The format of a typical entry is given in Fig. 1, and shows the individual types
of data that may be present in an entry.

Chemical names and synonyms

All the names discussed below can be searched using the Chemical Name field.
Compounds have been named so as to facilitate access to their factual data by
keeping the nomenclature as simple as possible, whilst still adhering to good
practice as determined by IUPAC (the International Union of Pure and Applied
Chemistry). A great deal of care has been taken to achieve this aim as nearly as
possible. Some intentional departures from IUPAC terminological principles are
occasionally made to clarify the nomenclature of natural products. For example,
compounds containing both lactone and –COOH groups are often named using
two principal functional groups:
7
COOH

3
O
9

O
p-Menthan-9,3-olid-7-oic acid

4
 DNP name Laudanosine

MeO
MeO NMe
Structural formula
H
OMe
(S)-form
OMe

Alternative names N-Methyltetrahydropapaverine. Laudanine methyl ether

CDG36-H

Molecular Formula C 21H27NO4 M 357.449. Molecular weight

(R)-form: CDG37-I [85-63-2]

Synthetic. Mp 83–85 °. [α]D20 – 85 (c, 0.45 in EtOH).
Stereoisomer (S)-form: CDG39-K [2688-77-9] CAS Registry
descriptor Classification: VX2320. Number
Alkaloid from Papaver somniferum and Argemone grandiflora. (Papaveraceae).
Major metabolite of the neuromuscular blocker atracurium. Convulsive agent
Source data
acting on the extrapyramidal system and mesencephalon. Mp 89 °.
[ α]D25 + 103 (EtOH). [α]D + 52 (CHCl3).
Methiodide: CDG38-J Mp 225–227° (218–221°). [α]D + 120. Physical
(±)-form: CDG40-E [1699-51-0] data
Synthetic. Mp 114–115 ° (67–70°).
Hazard Alert symbol NX5070000 RTECS® Number
Supplier: Aldrich 10467-1; Sigma L1389. Supplier data
Derivative descriptor Hydrochloride: CDG41-F Mp 123°.

Aldrich Library of 13C and 1H FT NMR Spectra, 2, 667C (nmr)

Aldrich Library of FT-IR Spectra, 1st edn., 1, 1318A (ir)
Cymerman-Craig, J et al., Tetrahedron, 1996, 22, 1335 (uv, ord, config)
Elliot, IW, J. Het. Chem., 1970, 7, 1229 (synth)
Preininger, V, Alkaloids (N.Y.), 1975, 15, 207 (pharmacol)
Konda, M et al., Chem. Pharm. Bull, 1975, 23, 1025; 1977, 25, 69 (synth, ir, pmr, ms)
Singh, SP et al., J. Het. Chem., 1978, 15, 541 (cmr)
Bibliographic
Takano, S et al., Chem, Comm., 1982, 22, 769 (synth)
references
Czarnocki, Z et al., Can. J. Chem., 1986, 64, 2205 (synth)
Gawley, RE et al., Tet. Lett., 1988, 29, 301 (synth) Reference
Gottlieb, L et al., J.O.C., 1990, 55, 5659 (synth) contents
Coppola, GM, J. Het. Chem, 1991, 28, 1769 (synth)
Comins, DL et al., Heterocycles, 1991, 32, 2995 (synth)
Takano, S et al., Tet. Lett., 1993, 35, 47 (synth)
Martindale, The Extra Pharmacopoeia, 30th edn., Pharmaceutical Press, London, 1993, 1200
Kitamura, M et al., J.O.C., 1994, 59, 297, (synth)

Fig. 1. Sample entry from database

(a) There are many instances in the primary literature of compounds being
named in ways which are gross violations of good IUPAC practice, e.g., where
the substituents are ordered non-alphabetically. These have been corrected.
(b) The number of trivial names used for acylating substituents has been kept
to a minimum but the following are used throughout.

H CO— H3C CO—

C C C C
H3C CH3 H CH3

Tigloyl = E-2-methyl- Angeloyl = Z-2-methyl-

2-butenoyl 2-butenoyl

Ph H
C C
H CO—

Cinnamoyl = 3-phenyl-2-propenoyl

Many other trivial appellations have from time to time appeared in the
literature for other acyl groups (e.g., Senecioyl = 3-methyl-2-butenoyl,

5
Feruloyl = 3-(4-hydroxy- 3-methoxyphenyl)-2-propenoyl or 4-hydroxy-
3-methoxycinnamoyl) but the systematic forms are usually employed except in
a few cases where the shortened form is used to abbreviate a very long and
unwieldy derivative descriptor as much as possible (e.g., for some of the
complex flavonoid glycosides).
(c) The term prenyl for the common 3-methyl-2-butenyl substituent,
(H3C)2C=CHCH2–, is used throughout.
(d) Names which are known to be duplicated within the chemical literature
(not necessarily within DNP), are marked with the sign†.

CAS Registry Numbers

CAS Registry Numbers are identifying numbers allocated to each distinctly
definable chemical substance indexed by the Chemical Abstracts Service since
1965 (plus retrospective allocation of numbers by CAS to compounds from the
sixth and seventh collective index periods). The numbers have no chemical
significance but they provide a label for each substance independent of any
system of nomenclature.
In DNP, much effort has been expended to ensure that accurate CAS numbers
are given for as many substances as possible.
If a CAS number is not given for a particular compound, it may be (a)
because CAS have not allocated one, (b) very occasionally, because an editorial
decision cannot be made as to the correct number to cite, or (c) because the
substance was added to the DNP database at a late stage in the compilation
process, in which case the number will probably be added to the database soon.
At the foot of the DNP entry, immediately before the references, may be
shown additional registry numbers. These are numbers which have been
recognised by the DNP editors or contributors as belonging to the entry
concerned but which cannot be unequivocally assigned to any of the compounds
covered by the entry. Their main use will be in helping those who need to carry
out additional searches, especially online searches in the CAS or other
databases, and who will be able to obtain additional hits using these numbers.
Clearly, discretion is needed in their use for this purpose.
Additional registry numbers may arise for a variety of reasons:
(a) A number may refer to stereoisomers or other variants of the main entry
compound or its derivatives, which may or may not be mentioned in the entry
but for which no physical properties or other useful information is available.
For example, the DNP entry for Carlic acid [56083-49-9] states that it has so
far been obtained in solution as a mixture of (E) and (Z)-forms. The additional
registry numbers given are those of the (E) and (Z) isomers [67381-73-1] and
[67381-74-2].
(b) A CAS number may refer to a mixture, in which case it is added to the
DNP entry referring to the most significant component. It may refer to a
hydrate, salt, complex, etc. which is not described in detail in the DNP entry.
(c) Replaced numbers, duplicate numbers and other numbers arising from
CAS indexing procedure or, occasionally, from errors or inconsistencies by
CAS, are also reported. For example, the DNP entry scyllo-Inositol [488-59-5]
contains an additional registry number for D-scyllo-Inositol [41546-32-1]. Since
scyllo-Inositol is a meso-compound, the number is erroneous. More generally,
CAS frequently replace a given number with one that more accurately
represents what they now know about a substance, and the replaced number
remains on their files and is given in DNP as an additional number.
(d) In the case of compounds with more than one stereogenic centre,
additional registry numbers frequently refer to levels of stereochemical

6
description which cannot be assigned to a particular stereoisomer described in
the entry.
For example, the CHCD entry for 2-Amino-3-hydroxy-3-phenylpropanoic
acid (β-Hydroxyphenylalanine, 9CI) has a general CAS number [1078-17-7]
and CAS numbers for all four optically active diastereoisomers [7352-06-9,
32946-42-2, 109120-55-0, 6524-48-4] as well as the two possible racemates
[2584-74-9] [2584-75-0]. However, among the additional registry numbers
quoted are the following:
[7687-36-7] – number for erythro-β-Hydroxyphenylalanine
[50897-27-3] – number for β-Hydroxy-L-phenylalanine
[68296-26-4] – number for β-Hydroxy-D-phenylalanine
[39687-93-9] – general number for the methyl ester, hydrochloride which
cannot be placed under any of the individual stereoisomers of
this compound described in the entry.
(e) Numbers may refer to derivatives similar to those described in the DNP
entry for which no data is available, or which have not yet been added to the
entry.
(f) Some DNP entries refer to families of compounds, such as the entry for
Calcitonin where only the porcine and human variants are described in detail.
The additional registry numbers given in this entry are those of a number of
other species variants which appear to have been identified according to CAS
but for which no attempt has been made to collate full data for DNP.

Diagrams
In each entry display there is a single diagram which applies to the parent entry.
Separate diagrams are not given for variants or derivatives.
Every attempt has been made to present the structures of chemical substances
as accurately as possible according to current best practice and IUPAC
recommendations. In drawing the formulae, as much consistency as possible
between closely related structures has been aimed at. Thus, for example, sugars
have been standardised as Haworth formulae and, wherever possible in complex
structures, the rings are oriented in the standard Haworth manner so that
structural comparisons can quickly be made. In formulae the pseudoatom
abbreviations Me, Et and Ac for methyl, ethyl and acetyl respectively, are used
only when attached to a heteroatom. Ph is used throughout whether attached to
carbon or to a heteroatom. Other pseudoatom abbreviations such as Pri for
isopropyl and Bz for benzoyl are not used in DNP.
Care must be taken with the numbering of natural products, as problems may
arise due to differences in systematic and non-systematic schemes. Biogenetic
numbering schemes which are generally favoured in DNP may not always be
contiguous, e.g., where one or more carbon atoms have been lost during
biogenesis.
Structures for derivatives can be viewed in Structure Search, but remember
that these structures are generated from connection tables and may not always
be oriented consistently.

Stereochemical conventions
Where the absolute configuration of a compound is known or can be inferred
from the published literature without undue difficulty, this is indicated. Where
only one stereoisomer is referred to in the text, the structural diagram indicates
that stereoisomer. Wherever possible, stereostructures are described using the
Cahn-Ingold-Prelog sequence-rule (R,S) and (E,Z) conventions but, in cases
where these are cumbersome or inapplicable, alternatives such as the

7
α,β-system are used instead. Alternative designations are frequently presented
in such cases.
The structure diagrams for compounds containing one or two chiral centres
are given in DNP as Fischer-type diagrams showing the stereochemistry
unequivocally. True Fischer diagrams in which the configuration is implied by
the North-South-East-West positions of the substituents are widespread in the
literature; they are quite unambiguous but need to be used with caution by the
inexperienced. They cannot be reoriented without the risk of introducing errors.
COOH COOH COOH COOH
H2N C H H2N C H or H2N H or H2N
CH3 CH3 CH3 CH3
DNP representation True Fischer projections

Where only the relative configuration of a compound containing more than

one chiral centre is known, the symbols (R*) and (S*) are used, the lowest-
numbered chiral centre being arbitrarily assigned the symbol (R*).
For racemic modifications of compounds containing more than one chiral
centre the symbols (RS) and (SR) are used, with the lowest-numbered chiral
centre being arbitrarily assigned the symbol (RS). The racemate of a compound
containing one chiral centre only is described in DNP as (±)-.
In comparing CAS descriptors with those given in DNP, it is important to
remember that the order of presentation of the chirality labels in CAS is itself
based on the sequence rule priority and not on any numbering scheme, for
example the CAS descriptor for the structure illustrated is [S-(R*,S*)].
COOH
2
H C NH2
3
HO C H
Ph

The relative stereochemical label (R*,S*) is first applied with the R* applying
to the chiral centre of higher priority (C-3). The absolute stereochemical
descriptor (S)- is then applied changing R* to S for the chiral centre of higher
priority and S* to R for the chiral centre of lower priority (C-2). For further
details, see the current CAS Index Guide.
For simplicity, the enantiomers of bridged-ring compounds, such as camphor,
are described simply as (+)- and (–)-. Although camphor has two chiral centres,
steric restraints mean that only one pair of enantiomers can be prepared.
For further information on the (R,S)-system, see Cahn, R,S et al, J. Chem.
Soc., 1951, 612; Experientia, 1956, 12, 81; Angew. Chem. Int. Ed. Engl., 1966,
5, 383.
Where appropriate, alternative stereochemical descriptors may be given using
the D, L or α,β-systems. For a fuller description of these systems, consult The
Organic Chemist's Desk Reference (Chapman & Hall, 1995).

Molecular formula and molecular weight

The elements in the molecular formula are given according to the Hill
convention (C, H, then other elements in alphabetical order). The molecular
weights given are formula weights (or more strictly, molar masses in daltons)
and are rounded to one place of decimals. In the case of some high molecular
mass substances such as proteins the value quoted may be that taken from an
original literature source and may be an aggregate molar mass.
Molecular formulae are included in DNP for all derivatives which are natural
products and so are readily searchable, whether they are documented as
derivatives or have their own individual entry. Molecular formulae are not in

8
general given for salts, hydrates or complexes (e.g. picrates) nor for most
"characterisation" derivatives such as acetates and methyl ethers of complex
natural products.
Where a derivative appears to have characterised only as a salt, the properties
of the salt may be given under the heading for the derivative. In such cases the
data is clearly labelled, e.g., Mp 179° (as hydrochloride).

Source
The taxonomic names for organisms given throughout are in general those given
in the primary literature. Standardisation of minor orthographical variations has
been carried out. Data in this field may be searched under Source/Synthesis or
All Text. Standards used are: Brummitt, R.K. (1992) Vascular Plant Families
and Genera, Royal Botanic Gardens, Kew; Willis, J.C. (1973) A Dictionary of
the Flowering Plants, Cambridge University Press, Cambridge; Gozmany, L.
(1990) Seven Language Thesaurus of European Animals, Chapman & Hall
London; Chemical Abstracts Service.

Importance/use
Care has been taken to make the information given on the importance and uses
of chemical substances as accurate as possible. Data in this field may be
searched under Use/Importance or All Text.

Type of Compound
All natural products are classified under one of more than 1050 headings
according to structural type, e.g., daucane sesquiterpenoid, pyrrolizidine
alkaloid, withanolide. Each structural type is assigned as a type of compound
code, e.g., VG0300, VX0150. Type of compound words and type of compound
codes may both be searched in Menu and Command search.
The full type of compound code index is given in Table 3, page 128 of the
printed User Manual, and in the Description of Natural Product Structures that
follows, each descriptive paragraph is followed by its Type of Compound
code(s).

Physical Data
Appearance
Natural products are considered to be colourless unless otherwise stated. Where
the compound contains a chromophore which would be expected to lead to a
visible colour, but no colour is mentioned in the literature, the DNP entry will
mention this fact if it has been noticed by the contributor.
An indication of crystal form and of recrystallisation solvent is often given
but these are imprecise items of data; most organic compounds can be
crystallised from several solvent systems and the crystal form often varies. In
the case of the small number of compounds where crystal behaviour has been
intensively studied (e.g. pharmaceuticals), it is found that polymorphism is a
very common phenomenon and there is no reason to believe that it is not
widespread among organic compounds generally.

Melting points and boiling points

The policy followed in the case of conflicting data is as follows:
(a) Where the literature melting points are closely similar, only one figure
(the highest or most probable) is quoted.

9
 (b) Where two or more melting points are recorded and differ by several
degrees (the most likely explanation being that one sample was impure), the
lower figure is given in parentheses, thus: 139° (134–135°).
(c) Where quoted figures differ widely and some other explanation such as
polymorphism or incorrect identity seems to be the most likely explanation,
both figures are quoted without parentheses, thus Mp 142°, Mp 205–206°.
(d) Known cases of polymorphism or double melting point are noted.
Boiling point determination is less precise than that of melting points and
conflicting boiling point data is not usually reported except when there appears
to be a serious discrepancy between the different authors.

Optical rotations
These are given whenever possible, and normally refer to what the DNP
contributor believes to be the best-characterised sample of highest chemical and
optical purity. Where available an indication of the optical purity (op) or
enantiomeric excess (ee) of the sample measured now follows the specific
rotation value.
Specific rotations are dimensionless numbers and the degree sign which was
formerly universal in the literature has been discontinued.

Densities and refractive indexes

Densities and refractive indexes are now of less importance for the identification
of liquids than has been the case in the past, but are quoted for common or
industrially important substances (e.g. monoterpenoids), or where no boiling
point can be found in the literature.
Densities and refractive indexes are not quoted where the determination
appears to refer to an undefined mixture of stereoisomers.

Solubilities
Solubilities are given only where the solubility is unusual. Typical organic
compounds are soluble in the usual organic solvents such as ether and
chloroform, and virtually insoluble in water. The presence of polar groups (OH,
NH2 and especially COOH, SO3H, NR+) increases water solubility.

pKa values
pKa values are given for both acids and bases. The pKb of a base can be
obtained by subtracting its pKa from 14.17 (at 20°) or from 14.00 (at 25°).

Spectroscopic data
Spectroscopic data such as uv wavelengths and extinction coefficients are given
only where the spectrum is a main point of interest, or where the compound is
unstable and has been identified only by spectroscopic data.
In many other cases, spectroscopic data can be rapidly located through the
references quoted.

Hazard and toxicity information

General
Toxicity and hazard information is highlighted by the sign , and has been
selected to assist in risk assessments for experimental, manufacturing and
manipulative procedures with chemicals.

10
 The field of safety testing is a complex, difficult and rapidly expanding one,
and while as much care as possible has been taken to ensure the accuracy of
reported data, the Dictionary must not be considered a comprehensive source on
hazard data. The function of the reported hazard data is to alert the user to
possible hazards associated with the use of a particular compound, but the
absence of such data cannot be taken as an indication of safety in use, and the
Publishers cannot be held responsible for any inaccuracies in the reported
information, neither does the omission of hazard data in DNP imply an absence
of this data from the literature. Widely recognised hazards are included
however, and where possible key toxicity reviews are identified in the
references. Further advice on the storage, handling and disposal of chemicals is
given in The Organic Chemist's Desk Reference.
Finally, it should be emphasised that any chemical has the potential for harm
if it is carelessly used. For many newly isolated materials, hazardous properties
may not be apparent or may have been cited in the literature. In addition, the
toxicity of some very reactive chemicals may not have been evaluated for
ethical reasons, and these substances in particular should be handled with
caution.

RTECS® Accession Numbers*

Many entries in DNP contain one or more RTECS® Accession Numbers. Pos-
session of these numbers allows users to locate toxicity information on relevant
substances from the NIOSH Registry of Toxic Effects of Chemical Substances,
which is a compendium of toxicity data extracted from the scientific literature.
For each Accession Number, the RTECS® database provides the following
data when available: substance prime name and synonyms; date when the
substance record was last updated; CAS Registry Number; molecular weight
and formula; reproductive, tumorigenic and toxic dose data; and citations to
aquatic toxicity ratings, IARC reviews, ACGIH Threshold Limit Values,
toxicological reviews, existing Federal standards, the NIOSH criteria document
program for recommended standards, the NIOSH current intelligence program,
the NCI Carcinogenesis Testing Program, and the EPA Toxic Substances
Control Act inventory. Each data line and citation is referenced to the source
from which the information was extracted.

Bibliographic References
The selection of references is made with the aim of facilitating entry into the
literature for the user who wishes to locate more detailed information about a
particular compound. Thus, in general, recent references are preferred to older
ones, particularly for chiral compounds where optical purity and absolute
configuration may have been determined relatively recently. The number of
references quoted cannot therefore be taken as an indication of the relative
importance of a compound, and the references quoted for important substances
may not be the most significant historically.
References are given in date order except for references to spectroscopic
library collections, which sort at the top of the list, and those to hazard/toxicity
sources which sort at the bottom.
The content of most references is indicated by means of suffixes, known as
reference tags. A list of the most common ones is given in Table 4, p. 145 of the
printed User Manual. For references describing a minor natural product which
has been included in DNP as a derivative of a parent compound, the reference
tag may be the identifying name of the natural product, e.g. (Laciniatoside II).
*RTECS® Accession Numbers are compiled and distributed by the National Institute for Occupational Safety and Health Service
of the U.S. Department of Health and Human Services of The United States of America. All rights reserved. (1996)

11
 Some reference suffixes are now given in boldface type, where the editors
consider the reference to be particularly important, for example the best
synthesis giving full experimental details and often claiming a higher yield than
previously reported methods.
In some entries, minor items of information, particularly the physical
properties of derivatives, may arise from references not cited in the entry.

Journal abbreviations
In general these are uniform with the Chemical Abstracts Service Source Index
(CASSI) listing except for a short list of very common journals:

DNP ABBREVIATION CASSI

Acta Cryst. Acta Crystallogr.
(and sections thereof) (and sections thereof)
Annalen Justus Liebigs Ann. Chem.
Chem. Comm. J. Chem. Soc., Chem. Commun.
J.A.C.S. J. Am. Chem. Soc.
J.C.S. (and various J. Chem. Soc. (and various
subsections thereof) subsections thereof)
J. Het. Chem. J. Heterocycl. Chem.
J.O.C. J. Org. Chem.
Tet. Lett. Tetrahedron Lett

Entry under review

The database is continually updated. When an entry is undergoing revision at
the time of a CD-ROM release (for example by the addition of further
derivatives or references), this is indicated by a message at the head of the entry.

12
Description of
Natural Product Structures
This Description of Natural Product Structures is adapted from the printed
version of Dictionary of Natural Products, and revised for Dictionary of
Natural Products on CD-ROM
The purpose of this general introduction and review is to facilitate access to
the DNP Type of Compound Index which in turn leads on to the individual
DNP entries. The order of main sections is the same as in the Type of
Compound Index, and within the main sections the order of description of types
of compound in general parallels the order in which they appear in the Type of
Compound Index (except in the case of aliphatic natural products). Throughout
this Description, the names of natural products which are not specially
illustrated here but which are documented in DNP entres are given in boldface
type. (The names used in this Description may not necessarily be the Dictionary
entry names: use the Compound Name Index to locate substances if necessary.)
The various classes of natural product are described in respect of: (a)
structural characteristics; (b) nomenclature, including Chemical Abstracts
nomenclature; (c) biogenesis; (d) general biochemical significance and (e) any
other information about the class which is of general importance. For detailed
information about individual natural products it is necessary to locate the
compound within its entry, which will in turn facilitate access to the primary
literature.

Contents
Aliphatic natural products page 15
Semiochemicals 15
Lipids 22

Polyketides 29

Carbohydrates 35

Oxygen heterocycles 44

Simple aromatic natural products 45

Benzofuranoids 48

Benzopyranoids 49

Flavonoids 51

Tannins 60

Lignans 64

Polycyclic aromatic natural products 68

13
Terpenoids page 72
Monoterpenoids 73
Sesquiterpenoids 77
Diterpenoids 101
Sesterterpenoids 118
Triterpenoids 121
Tetraterpenoids 131
Miscellaneous terpenoids 133
Meroterpenoids 133

Steroids 135
The sterols 140

Aminoacids and peptides 148

Aminoacids 148
Peptides 150
β-Lactams 151
Glycopeptides 153

Alkaloids 154
Alkaloids derived from ornithine 154
Alkaloids derived from lysine 156
Alkaloids derived from nicotinic acid 158
Alkaloids of polyketide origin 159
Alkaloids derived from anthranilic acid 160
Alkaloids derived wholly or in part from phenylalanine or
tyrosine 163
Isoquinoline alkaloids 163
Alkaloids derived from tryptophan 181
Monoterpenoid indole alkaloids 184
Terpenoid alkaloids 196
Steroidal alkaloids 200
Imidazole alkaloids 202
Oxazole alkaloids 202
Thiazole alkaloids 203
Pyrazine and quinoxaline alkaloids 203
Pyrrole alkaloids 203
Putrescine alkaloids 203
Spermine and spermidine alkaloids 203
Peptide alkaloids 204
Purines 205
Pteridines and analogues 205

Polypyrroles 206

14
Aliphatic natural products (VA)
A wide variety of small aliphatic and alicyclic compounds occur in nature.
Because they are diverse, no attempt will be made here to give a general
account; for information on specific aliphatics, their individual entries should be
consulted. Accounts are given below, however, of the semiochemicals, which
are structurally diverse but which are defined functionally and include many of
the aliphatic compounds of greatest biochemical importance and current
research interest, and of the lipids, which are structurally more or less well
defined.
In the Type of Compound Index, the aliphatic compounds included in the
Dictionary are simply classified by functional group and ring/chain structure.
A wide range of aliphatic compounds is documented as secondary products
from natural starting materials, e.g. in cooked foods, but these are outside the
scope of the Dictionary.

Semiochemicals
Semiochemicals are defined as chemicals that mediate communication between
individual organisms. The word is derived from the Greek word semeion which
means mark, sign or signal. Although some semiochemicals are released
purposefully (sex pheromones, the scent of flowers), others are released as a
consequence of normal metabolism, but nevertheless still convey information.
An example of the latter is the attraction of the tsetse fly to carbon dioxide in
the breath of cattle. It is of no consequence whatsoever to the fly that the
‘signal’ is intentional or otherwise.
Most workers exclude the consumption of food (but not its detection) and the
use of defence chemicals but again not their subsequent detection (cf. the stink
of the skunk) as semiochemical interactions. The study of semiochemical
interactions is termed chemical ecology. An alternative nomenclature
emphasises the transfer of information, and uses the term infochemical, instead
of semiochemical.
When semiochemicals act between members of the same species they are
known as pheromones from the Greek pherein to carry and horman to excite or
stimulate. They are the external counterparts of hormones which act as mes-
sengers between organs in the body. Pheromones have been divided into two
categories based on temporal criteria. Releaser pheromones elicit a response
which is immediate and usually behavioural, whereas primer pheromones cause
longer term physiological changes.
Pheromonal systems are usually the most highly developed semiochemical
systems because the species directly benefits from any improvement. Highly
developed in this context means that release of the pheromone is efficient and
timely and that the receiver has a sensitive and selective detection system.
Moreover because most pheromones are involved in reproductive functions
(mate attraction, courtship and copulation), increased efficacy is immediately
apparent in higher fecundity.
Semiochemicals that act between members of different species are called
allelochemics and these are further divided into allomones which cause an effect
favouring the emitter (such as the stink of the skunk) and kairomones which
favour the receiver (e.g. the odour of a prey species that attracts its predator).
Semiochemicals which favour both the receiver and the emitter are known as
synomones. A good example of this is the scent of a flower which attracts bees
to feed on nectar and pollinate them.
The most widely known semiochemicals are the volatile sexual attraction

15
pheromones of insects but volatility, although common, is not a prerequisite.
Semiochemicals may also be transferred by touch (e.g. the aphrodisiac
polypeptides of the golden hamster) or in solution (fish maturation factors).
They range in structure from carbon dioxide, ethylene (an attractant for bark
beetles), aliphatics, mono and polycyclic hetero and carbocycles through
steroids to polypeptides. All classes of organisms including yeast, corals,
crustacea, newts, fungi, plants, insects, spiders, mites, fish and mammals
employ some form of semiochemical. However only limited information is
available for amphibians, reptiles and birds.

Insect pheromones
There has been much interest in the use of insect pheromones for the monitoring
and control of insect pests in the field, gardens, stored products, food processing
factories and in commercial kitchens.
Semiochemicals of social insects, ants, termites, locusts, heteroptera and the
coniferphagus choristoneura have been reviewed (see bibliography); other
representative classes are reviewed below.
The structures of more lepidopteran pheromones are known than all other
pheromones together and moreover they are chemically fairly homogenous.
Typically they consist of an unbranched carbon chain with an even number of
carbon atoms, terminated by an oxygen containing group (acetate, alcohol or
aldehyde) with 0–4 alkenic bonds located predominantly towards the
hydrocarbon terminus of the chain.
The 1992 compilation of attractants for lepidoptera and other species by Arn
et al. includes 2292 semiochemicals from 1068 species, but only 264 unique
chemical structures. The most common attractants are Z9–14Ac (168 cases),
Z11–14Ac (157), Z11–16Ac (133), E11–14Ac (124) and Z7–12Ac (111).
Taken together these five chemicals are used by 30% of all species; however
80% of species use at least two components. Approximately 40% of the
structures have a terminal acetate group and the remaining 60% are evenly
divided between aldehydes, alcohols and hydrocarbons with a few 2-ketogroups.
Recently a nitrate terminal group was reported and presumably others remain to
be discovered. The commonest chain lengths in decreasing order of abundance
are C14, C12, C16 and C18. Approximately 40% are monoenes and 40%
dienes, with the double bonds predominantly located at the (ω-3) and (ω-5)
positions.
The biosynthesis of lepidopteran pheromones is controlled by a neuropeptide
(PBAN, pheromone biosynthesis activating neuropeptide). The pathway
commences with saturated fatty acids which undergo desaturation and
successive losses of terminal acetate units, followed by modification of the
terminal group. ∆9 and ∆11 desaturases for dodecanoic and tetradecanoic acids
(e.g. Bombykol) have been identified.
Methyl substituted straight-chain pheromones are fairly common in nature.
These range from simple systems with a sole methyl group remote from any
functionality or at the antiso position (ω-2) through n, (n + 6) and the more
common n, (n + 4) dimethyl compounds.
It is notable that n, (n + 4) polymethyl compounds have predominantly the
R-configuration. This results from incorporation of propionate into the normal
fatty acid biosynthetic pathway, in which the 2-pro-R proton is removed from
propionate. An interesting example which has been investigated in considerable
detail is 4R,8R-Dimethyldecanal, the aggregation pheromone of flour beetles.
2,6-Dichlorophenol is the female-produced pheromone for a number of ticks.
Several other species use Phenol and p-Cresol. However these are frequently
insufficient to elicit mating and a contact pheromone, Cholesteryl oleate, has
been identified from the American dog tick.

16
 The aggregation pheromone of the acarid mite Lardoglyphus konoi is
Lardolure.
Fruit flies (Diptera) and some species of wasp (Hymenoptera) use simple
spiroketals as sex pheromones. 1,7-Dioxaspiro[5.5]undecane is the major
female produced sex attractant of the olive fly Bactrocera oleae (formerly
Dacus oleae). Two other minor components, the 3-hydroxy and 4-hydroxy
derivatives were also identified.
Simple spiroketal ring systems have also been identified as the structural
motif of a wide range of other pheromones, e.g. rectal gland secretions of male
Asian fruit flies, Chalcogran, the aggregation pheromone of the bark beetle
Pityogenes chalcographus, aggression inhibiting pheromones of the wasp
Paravespula vulgaris, sexual attractants of several species of Andrena bees and
cephalic secretions of cleptoparasitic bees.
Attack of a tree by a bark beetle is orchestrated by a complex score of
semiochemical notes. Initial attack by pioneers (females in monogamous
species) occurs in response to tree volatiles such as Myrcene. Upon landing
gallery excavation commences, followed by mating and release of pheromones
by the males. The synergistic blend of tree volatiles and the pheromones
produced by both sexes initiates mass attack, which overwhelms the tree’s
defences. Meanwhile fungal and yeast spores are introduced into the tree
adventitiously or from special chambers (mycangi) on the shoulders of the
beetles. These micro-organisms proliferate and block the sap channels which
prevents the galleries being flooded with resin and may produce the beetles’
aggregation pheromone. In some species such as the ambrosia beetle the larvae
feed on the fungus. Finally when the tree is fully colonised deterrent phero-
mones are produced by the beetle, or by the fungi.
Bridged spiroketals are predominantly found as pheromones of bark beetles
and usually have a 6,8-dioxabicyclo[3.2.1]octane skeleton. The first structure to
be elucidated was that of Brevicomin, the female-produced aggregation
pheromone of the western pine beetle, Dendroctonus brevicomis. Different
beetle species produce different isomeric Brevicomin compositions. Male
western pine beetles produce Frontalin which is the last component to be added
to the synergistic blend of exo-Brevicomin and Myrcene (from the host tree)
which initiates mass attack of the host tree by the beetles.
Some other notable examples are Multistriatin, the pheromone of the
European elm bark beetle, Scolytus multistriatis, responsible for ‘Dutch Elm’
disease, the male-produced pheromones of the swift moth, Hepialus hecta
which are one carbon higher homologues of the bark beetle pheromones
described above, and Lineatin which has the same carbon skeleton as
Grandisol.

Rodents
The behaviour and development of the house mouse (Mus musculus) is deter-
mined by a complex system of pheromonal effects mostly mediated by urine.
The best characterised of these are 3,4-Dehydro-exo-brevicomin and 2-sec-
Butyl-2-thiazoline which are testosterone-dependant aggression promotors,
isolated from the urine of adult male mice. One of the most interesting
developmental factors is the acceleration of puberty by volatiles from adult
urine. Recent evidence suggest that 3,4-Dehydro-endo-brevicomin is bound to a
lipocalin (a small peptide) in mouse urine. When the urine is deposited it
releases the volatile ligand which promotes investigation by other mice. When
immature mice pick up the lipocalin it accelerates development into puberty.
Dimethyl disulfide has been identified in male rabbit pellets and rat preputial
tissue. It is released in the vaginal secretions of the female hamster and acts as a
potent attractant.

17
Fish
The sexual development of many species of fish is determined by the presence
of steroids in the water. 17α, 20β-Dihydroxypregn-4-en-3-one is detected by
the medial olfactory tracts of male goldfish and causes gonadotrophin secretion.
The in vitro biosynthesis of several steroids has been demonstrated in the
ovaries of the female during the final stages of oocyte maturation. Male Atlantic
salmon are similarly affected by the corresponding 20-sulfate and Test-
osterone.

Herbivores
Hoofed mammals have many specialised glands for scent marking. The tail
gland in the red deer (Cervus elaphus) produces Phenol, m-Cresol, Benzoic
acid, 4-Ethylphenol, Dimethyl sulfone, o-Cresol, 3-Phenylpropanoic acid
and Phenylacetic acid. Many of these are common to other herbivore and
carnivore species.
Herbivores avoid areas which carnivores have marked. Treatment of conifer
saplings with red fox urine, a synthetic mixture of its volatile constituents or
Isopentenyl methyl sulfide suppressed feeding on the saplings by the snowshoe
hare (Lepus americanus); which is common prey for the red fox in winter.
Similarly trees in orchards were protected from feeding by voles and gophers by
these materials and by 2,5-Dihydro-2,4,5-trimethylthiazole, a constituent of
red fox faeces. (Z)-7-Dodecenyl acetate which is best known as a lepidopteran
sexual attractant in at least 111 species, is also produced by female elephants at
the time of ovulation.

Carnivores
The Carnivores (dogs, cats etc.) show a wide range of social behaviour ranging
from solitary individualism to hunting in packs. Territory marketing with urine,
faeces and various glands is common and social interactions initiated by sniffing
are common even amongst habitually solitary species.
The characteristic ‘skunky odour’ of fox urine is due to Methyl 2-phenyl-
ethyl sulfide and Isopentenyl methyl sulfide, which is also a component of wolf
urine and comprises more than 50% of the volatiles from female coyote urine.
Bis(3-isopentenyl) sulfide and Isopentanethiol are also found in coyote urine
and reach a maximum at oestrus. The latter is also a component of the defensive
‘scent’ of the striped skunk, together with a series of crotyl thiols. 2,2-Di-
methylthietane (Mustelan) was isolated from the anal glands of the mink and
the polecat which also contains 3,3-Dimethyl-1,2-dithiolane and Bis(3-iso-
pentenyl) sulfide. (2S)-2-Propylthietane is the major malodorous substance
from the anal gland of the stoat (Mustela erminea).
The anal sacs of the red fox secrete a mobile strongly smelling liquid con-
taining a complex mixture of short chain carboxylic acids, Trimethylamine and
diamines such as Putrescine and Cadaverine. The volatile fatty acids are
produced by anaerobic bacteria.
The anal sacs of the dog (Canis familiaris) and the coyote (Canis latrans)
also contain short chain carboxylic acids and Trimethylamine. Carboxylic acids
and medium chain esters, plus Indole and Hexanol were found in the anal gland
secretion of the aardwolf (Proteles cristatus), but no aliphatic amines were
detected. Indole is also present in the anal sac secretion of the ferret (Mustelo
furo), but the components which elicit the greatest attraction for conspecifics are
2-Propylthietane, 3-Propyl-1,2-dithiolane and cis and trans-2,3-Dimethyl-
thietane.

18
 The supracaudal gland is present in most Canidae and is most highly
developed in the less social species. Sniffing the gland is common in social
interactions. The secretion of the gland has a floral odour and it is often
described as the ‘violet gland’. Dihydroactinidiolide and other volatile terpenes
have been detected in the distillate from the secretion of the red fox Vulpes
vulpes but very little is known about the other constituents.

Humans
The apocrine glands, which are mostly found in the armpit and on the head, are
believed to be the source of human pheromones. 5α-Androst-16-en-3-one (the
principal component of boar taint) and other steroids are secreted by males from
the armpits and modified by the microflora on the skin. Armpit extracts have
been shown to modify the menstrual cycle of women with irregular periods and
the curious phenomenon of menstrual synchronisation which occurs between
cohabiting women is believed to be mediated pheromonally. The odour of
steroids and the similar odour of musk has always played a significant role in
human culture, such as the base note of perfumes, the burning of incense and
the highly prized truffle.

Yeast
Saccharomyces cerevisiae (Bakers’ yeast) has two haploid mating types
designated as a and α which release the pheromones a-factor and α-factor
(respectively). These cause arrest of the cell cycle in the G1 phase and
development of pear shaped extrusions of the cell called shmoos. Agglutination,
cell fusion and nuclear fusion gives a zygote that produces a/α diploid buds.
Cells are able to discriminate amongst potential partners and select those with
the highest pheromone production. This has been termed courtship.
The genes MFα1 and MFα2 encode two α-factor precursors, consisting of
165 and 120 amino acids respectively. These are translocated into the classical
secretory pathway where they are glycosylated on asparagine and proteolysed to
give mature α-factor which is a 13 aminoacid peptide (WHWLQLKPGQPMY)
and released.
MFA1 and MFA2 are the two genes which encode 36 and 38 amino acid
peptide precursors of two forms of a-factor. They are synthesised and undergo
proteolysis in the cytoplasm to give 15-mers. These have a C-terminal -CAAX
motif, where C is Cysteine, A is an aliphatic aminoacid and X is variable. The
Cysteine undergoes S-farnesylation, the terminal tripeptide is cleaved, and
finally methylation of the terminal cysteine gives the a-factors (YIIKG(V or
L)FWDFA(S-Far)C-OMe). These both contain 12 aminoacid residues but differ
at residue 6.
The genes STE2 and STE3 encode the receptors for α and a-factor
respectively. The proteins are predicted to have seven potential transmembrane
domains, analogous to the β-adrenoceptor and rhodopsin receptors which
interact with mammalian G-proteins. Therefore G-proteins may also participate
in the mating signal transduction pathway in yeast.
Five unique pheromones have been identified from seven mating types of the
ciliated protozoa Euplotes raikovi. These consist of 38–40 aminoacid residue
polypeptides with an amino terminal aspartic acid residue and six conserved
half cystines, but otherwise they have little homology although Er-1189 and Er-
2 are bound equally well by some monoclonal antibodies. Different mating
types producing the same pheromone are able to mate and one type which
secretes Er-20 is unable to mate with any of the others.
Conjugative plasmid transfer by Enterococcus faecalis is induced by a
pheromone released by the prospective recipient.

19
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Algae
The marine brown algae have evolved a unique pheromone system, the known
members of which are based on a range of acyclic or aliheterocyclic alkenes.
The majority of these are C11, examples being the Dictyopterenes, exemplified
by Dictyopterene A and Desmarestene. Some Fucus and Sargassum species
employ the smaller molecule 1,3,5-Octatriene (various stereoisomers). These
molecules modulate the navigation of the male gametophytes in the marine
environment over the very short ranges (~1 mm) required for fertilisation. They
are biosynthesised from highly unsaturated fatty acids by pathways not yet
understood; the precursor unsaturated acids such as eicosahexaenoic, are of a
type not found in terrestrial plants.

Dictyopterene A Desmarestene

There are some known examples of low molecular-weight compounds fulfilling

a similar function in freshwater algae, but in these cases the pheromones are
terpenoid, as exemplified by Sirenin. In general, knowledge of pheromone
systems in lower plants is still too fragmentary to generalise that compounds of
these series represent all of the possibilities. This point is underlined by the

21
recent characterisation of Lurlene, of a totally different structural type, as the
sex pheromone of the terrestrial green flagellate alga Chlamydomonas
allensworthii.

Jaenicke, L. et al, Angew. Chem. Internat. Ed. Engl., 1982, 21, 643–653.
Wirth, D. et al, (1992), Helv. Chim. Acta, 75, 734–744.

Lipids
Lipids have been defined in different ways at different times and there is still no
agreed definition of the term. Recent proposals are based mainly on chemical
structure and, in turn, on the underlying biosynthetic pathways; two recent
definitions read: ‘lipids are fatty acids and their derivatives, and substances
related biosynthetically or functionally to these compounds’ and ‘lipids are
compounds based on fatty acids or closely-related compounds such as the fatty
alcohols and the sphingosine bases’. This definition includes all the major
groups of materials generally recognised as lipids: it incorporates sterol esters
but not the free sterols.

Fatty acids (VA0300, VA0600, VA1100, VA1500)

Many fatty acids are still known by their trivial names (e.g. Palmitic, Linoleic).
These were often related to the original source of the acid and were given
before the structure could be adequately defined.
Systematic names indicate the chain-length and the nature, position, and
configuration of unsaturated centres as in the following examples:

Trivial Systematic Abbreviation

Palmitic hexadecanoic 16 : 0
Oleic cis-9-octadecenoic 18 : 1 (9Z)
Arachidonic all-cis-5,8,11,14-eicosatetraenoic 20 : 4 (n-3)

The systematic names are often replaced by abbreviations of the form A:

B(C). A indicates the number of carbon atoms in the molecule, B represents the
number of unsaturated centres which are usually cis-(Z-) alkenic, and C
indicates the position and configuration of the unsaturation. Organic chemists
number the chain from the carboxyl group (COOH = 1) hence 9Z for oleic acid
but there are times when it is more appropriate to count from the methyl end
and to use symbols such as ω3 or n-3 to indicate the position of the unsaturated
centre closest to the CH3 group. In this case it is assumed that all unsaturation is
methylene – interrupted and has cis-(Z-) configuration.
The number of natural fatty acids which has been reported may exceed 1000
though only 20–50 are of common concern. From a survey of all these
structures it is possible to make a number of general statements. These are
essentially true, particularly in respect of the more common and important acids,
but there are significant exceptions to each statement. These statements were
first based on chemical structure but it is clear that they also reflect underlying
biosynthetic pathways.
(i) Natural fatty acids – both saturated and unsaturated – are straight-chain
compounds with an even number of carbon atoms. This holds for the great
majority of structures and for the more common acids. Chain lengths range from
two to more than eighty carbon atoms but are most commonly between C12 and
C22. Despite the validity of this generalisation acids with an odd number of
carbon atoms (e.g. Nonadecanoic) occur as do those with branched structures

22
(e.g. Isopalmitic, Anteisononadecanoic) or with carbocyclic units (e.g.
Sterculic).
(ii) Acids with one unsaturated centre are usually alkenic compounds with
cis- (Z-) configuration and with the double bond in one of a limited number of
preferred positions. This is most commonly ∆9 (e.g. Oleic) or n-9 (e.g. Erucic)
but the double bond can occur in other positions (e.g. Petroselinic) and
monoacetylenic acids are also known (e.g. Tariric).
(iii) Polyunsaturated acids are mainly poly-alkenic (cis-/Z-configuration) with
a methylene-interrupted arrangement of double bonds, i.e. double bonds are
separated from each other by one CH2 group. The pattern of 1,4-unsaturation is
characteristic of fatty acids and differs from that in isoprenoids which is usually
1,3-(conjugated) or 1,5-. Polyunsaturated fatty acids occur in biochemically
related families and the two most important are the n-6 family based on
Linoleic acid and the n-3 family based on α-Linolenic acid (see discussion on
biosynthesis below). Some acids have conjugated unsaturation which is both cis
and trans (e.g. Eleostearic, Calendic, Parinaric), some have mixed ene/yne
unsaturation both conjugated (e.g. Isanic) and non-conjugated (e.g.
Crepenynic), and there is a small group of acids in which unsaturation is not
entirely methylene-interrupted (e.g. Columbinic).
(iv) Fatty acids rarely have functionality apart from the carboxyl group and
the various types of unsaturation discussed above but acids are known with
fluoro, hydroxy, keto, and epoxy groups. Two important examples are
Ricinoleic (12-hydroxyoleic) and Vernolic (cis-12,13-epoxyoleic).
These generalisations have a biosynthetic basis and even some of the
exceptions can be accommodated in general biosynthetic schemes with only
minor modification.
The major biosynthetic pathways leading to fatty acids are summarised in
Figure 1. In the de novo pathway leading to saturated fatty acids, acetate (the
primer) condenses with malonate (the extender) to produce a C4 oxo acid which
is reduced in three steps to butanoate. This cycle of condensation and reduction
continues until, most commonly, palmitate has been obtained, though in lauric
oils rich in 12 : 0 the process stops mainly at the C12 level. The malonate is itself
derived from acetate by carboxylation in the presence of a biotin enzyme and
the carbon dioxide lost during condensation is that derived during carboxylation
so that the carbon atoms in butanoate and in the longer chain acids are entirely
acetate-derived.

a b
2:0 16:0 18:0
c b
n – 9 monoenes
b,c
18:1 n – 9 polyenes
d

b,c
18:2 n – 6 polyenes

b,c
18:3 n – 3 polyenes

a = de novo synthesis of saturated acids (mainly palmitic),

b = chain-elongation, c = ∆9-desaturation, d = desaturation
of ∆9-monoene (plants only), e = desaturation between an
existing double bond and the carboxyl group (occurs rarely
in plants but commonly in animals).

Figure 1. Fatty acid biosynthesis.

23
 If the acetate is replaced by a different primer then other fatty acids are
produced. This can be propionate (major product: heptadecanoate), 2-methyl-
propionate (iso acids), or 2-methylbutanoate (anteiso acids).
The chain-elongation process is similar in outline to the de novo process but
differs in some significant details. It operates with both saturated and
unsaturated acids and occurs with either acetate or malonate. Erucic acid is
made from Oleic acid by two chain-elongation steps:

18 : 1 (9Z) → 20 : 1 (11Z) → 22 : 1 (13Z)

Both Oleic acid and Erucic acid are n-9 monoenes. This chain-elongation process
is also important in the biosynthesis of polyenes (see below).
The most common route to monoene acids involves ∆9 desaturation. This
oxygen-requiring process occurs in plants, animals and microorganisms and
furnishes acids with a cis-double bond between carbon atoms 9 and 10, e.g. 9-
hexadecenoic, 9-octadecenoic (Oleic).
Further desaturation of Oleic acid to the 9,12-diene (Linoleic) and 9,12,15-
triene (α-Linolenic) occurs only in plants. The additional double bonds assume
a methylene interrupted pattern and lie between the existing double bond and
the methyl group. Animals requiring these acids for the production of n-6 and n-
3 polyene acids must obtain them through their dietary intake.
The bioconversion of 22 : 5 to 22 : 6 (and presumably of 22 : 4 to 22 : 5)
may occur by a more complicated pathway than that suggested in Figure 2
involving the sequence 22 : 5 → 24 : 5 (elongation) → 24 : 6 (desaturation) →
22 : 6 (chain shortening)
Desaturation between an existing double bond and the carboxyl group occurs
only rarely in plants (e.g. γ-Linoleic acid) but readily in animals. The additional
double bonds have cis- configuration and are introduced in a methylene-
interrupted pattern.
Some of these acids are required for the maintenance of health and are
designated essential fatty acids (efa). It is possible to produce efa deficiency in

n–6 n–3
Linolenic 18:2 18:3 α-Linolenic

desaturation

γ-Linolenic 18:3 18:4 Stearidonic

elongation

Homo-γ-linolenic 20:3 20:4 —

desaturation

Arachidonic 20:4 20:5 EPA*

elongation

— 22:4 22:5 —

desaturation

— 22:5 22:6 DHA*

*eicosapentaenoic and docosahexaenoic acids

Figure 2. The n-6 and n-3 families of polynsaturated acids based on Linoleic and α-
Linolenic acids.

24
experimental animals but this state is rarely observed in humans who generally
ingest adequate quantities of Linoleic and α-Linolenic acid. Efa deficiency is
most likely to be observed under conditions where the normal enzymic
processes – especially desaturation – are impaired.
A wide variety of unusual fatty acids and phospholipids are found in sponges,
and these arise by totally different biosynthetic pathways.

Oxylipins (VA6150)
Three C20 acids – 20 : 3 (n-6), 20 : 4 (n-6), and 20 : 5 (n-3) – are precursors of
the PG1, PG2 and PG3 series of prostaglandins and of many other C20 metabo-
lites. These are known collectively as eicosanoids and are products of the
eicosanoid cascade.
The term oxylipin has been coined relatively recently to describe the class of
natural product, of which prostaglandins are the most widespread, that are
produced from C20 and in some cases C18 fatty acid precursors in at least one
stage of mono- or dioxygenase-dependent oxidation. Since it is now known that
C20 precursors are not universal, the term oxylipin is to be preferred to the
previous term eicosanoid.
The widest variety of structural types is found in marine organisms where
ring formation may produce three- (e.g. Constanolactones), five (e.g.
Ecklonialactone A) or six- (e.g. Manzamenone A) membered rings.

MeOOC
H (CH2)15CH3
H3C(CH2)15
COOMe

H O
HOOC
Manzamenone A

Prostaglandins, prostacyclins and thromboxanes (VA6100)

The eicosanoid or arachidonic acid cascade produces Prostaglandins,
Prostacyclin and Thromboxanes that mediate a wide range of physiological
responses. They have short half lives and thus have limited clinical application,
however synthetic analogues are being used as drugs.
In mammals, the arachidonate-derived prostaglandins play an important role
in maintaining homeostasis.
Prostaglandins F2α and E2 are unexpectedly also encountered in marine algae
and invertebrates. It appears that at least in corals these arise via lipoxygenase
metabolism rather than the mammalian prostaglandin H synthase
(cyclooxygenase) pathway.

Baxter, A.D. et al. (1986) Chem. Ind. (London), 510 (synth).

Bentley, P.H. (1973) Chem. Soc. Rev., 2, 29 (synth).
Collins, P.W. et al. (1993) Chem. Rev., 93, 1533 (synth).
Djerassi, C. et al., Acc. Chem. Res., 1991, 24, 64 (sponges)
Gerwick, W.H. (1993), Chem. Rev., 93, 1807–1823 (marine oxylipins)
Hart, T.W. (1988) Nat. Prod. Rep., 5, 1.
Lai, S.M.F. et al. (1984) Nat. Prod. Rep., 1, 409.
Lands, W.E.M. (1991) Annu. Rev. Nutr., 11, 41 (biosynth).
Newton, R.F. et al. (1984) Synthesis, 449 (synth).
Smith, W.L. (1992) Am. J. Physiol., 263, F181 (biosynth, action).

25
Glycerides (VA6700, VA6800, VA6900)
Fatty acids occur naturally as esters of Glycerol or of some other hydroxy
compound or as amides of long-chain amines such as Sphingenine. The less
common long-chain alcohols occur as esters or as ethers. Triacylglycerols are
major storage lipids whilst phospholipids (see below) are important membrane
constituents.
Acylglycerols are esters of glycerol and fatty acids. Partial glycerides are
important intermediates in metabolism and triacylglycerols are the major
constituents of natural fats and oils. In DNP glycerides are named as glycerol
triesters, e.g. entry name = Glycerol tri-9-octadecenoate.
In order to designate the stereochemistry of glycerol-containing components,
the carbon atoms of glycerol are numbered stereospecifically. When the glycerol
molecule is drawn in a Fischer projection with the secondary hydroxyl group to
the left of the central prochiral carbon atom, then the carbons are numbered 1, 2
and 3 from top to bottom. Molecules which are stereospecifically numbered in
this fashion have the prefix ‘sn’ immediately preceding the term ‘glycerol’ in
the name of the compound to distinguish them from compounds which are
numbered in a conventional fashion. The prefix ‘rac’ in front of the full name
shows that the compound is an equal mixture of both antipodes and ‘x’ is used
if the configuration is unknown or unspecified.
Any glycerolipid will be chiral when the substituents at the sn-1 and sn-3
positions are different. If both substituents are long-chain acyl groups then the
optical rotation will be extremely small.
Monoacylglycerols (monoglycerides) (VA6700) are fatty acid monoesters of
glycerol and exist in two isomeric forms:

α1 CH2OOCR CH2OH

β2 HO C H RCOO C H

α′ 3 CH2OH CH2OH
1-Monoacyl-sn-glycerol 2-Monoacyl-sn-glycerol
(α-isomer) (β-isomer)

Diacylglycerols (diglycerides) (VA6800) are fatty acid diesters of glycerol

and also occur in two isomeric forms:

CH2OOCR1 CH2OOCR1

R2COO C H HO C H

CH2OH CH2OOCR2
1,2-Diacyl-sn-glycerol 1,3-Diacyl-sn-glycerol
(α,β-isomer) (α,α′-isomer)

Triacylglycerols (triglycerides) (VA6900) are fatty acid triesters of glycerol.

The fatty acids may be all different, two different, or all alike.

CH2OOCR1

R2COO C H

CH2OOCR3

Triacyl-sn-glycerol

These materials occur as mixtures with various acyl chains which may show
some fatty acid specificity. As a consequence particular fatty acids may be
concentrated in or excluded from particular positions in the glycerol ester. To
produce seed oils with more than 67% of a particular acid it may be necessary
to modify the acylating enzymes by genetic manipulation.

26
 sn-glycerol-3-phosphate

1-acyl-sn-glycerol-3-phosphatea

1,2-diacyl-sn-glycerol-3-phosphate

2-monoacyl-sn-glycerolb

1,2-diacyl-sn-glycerol

phospholipids
triacylglycerol
(PC, PE, PS)

a = also produced from dihydroxyacetone phosphate

b = produced from exogenous (dietary) triacylglycerols
by lipolysis.

Figure 3. Biosynthesis of the major lipid classes.

In plants glycerolipids are produced by wholly endogenous pathways but in

animals there are additional routes by which dietary lipids are modified. The
lipid composition of animals is influenced by dietary intake but is not
completely defined by it.
1,2-Diacyl-sn-glycerols (Figure 3) are key intermediates in the biosynthesis of
both triacylglycerols and phospholipids and are produced mainly from sn-
glycerol-3-phosphate (a product of carbohydrate metabolism) by acylation of
both free hydroxyl groups in separate stages followed by dephosphorylation.
Further acylation of the sn-3 hydroxyl group gives triacylglycerols.

Phospholipids and sphingolipids (VA7000, VA7200)

Phospholipids and sphingolipids are constituents of cell membranes and they
play an essential role in the synthesis of plasma lipoproteins and in the
transduction of messages from cell surfaces to second messengers that control
cellular processes. Phosphatidylcholine (Lecithin) is the most abundant
phospholipid.
Sphingenine – the most common of the long-chain bases – is produced from
Palmitic acid (as its CoA derivative) and Serine as shown in Figure 4. Such
compounds are then acylated at the NH2 group to give ceramides and further
modified at the primary hydroxyl group to give sphingolipids (Figure 5).

CH2OOCR1
R2COOCH O
CHOPOX
O–

X Name of class Abbreviation

H phosphatidic acid PA
+
CH2CH2N H3 phosphatidylethanolamine PE
+
CH2CH2N Me3 phosphatidylcholine PC
+
CH2CH(N H3)COOH phosphatidylserine PS
CH2CH(OH)CH2OH phosphatidylglycerol PG
C6H11O6 phosphatidylinositol PI

Figure 4. Structures of the major phospholipids.

27
 H3C(CH2)14COSCoA
palmitoyl-CoA

serine

H3C(CH2)14COCH(NH2)CH2OH
3-ketodihydrosphinganine

H3C(CH2)14CH(OH)CH(NH2)CH2OH
dihydrosphinganine

H3C(CH2)12CH=CHCH(OH)CH(NH2)CH2OH
sphingenine

Figure 5. Biosynthesis of Sphingenine.

E
H3C(CH2)12CH=CHCH(OH)CHCH2OR2

NHR1

sphingenine (R 1 = R2 = H)

ceramides (R 1 = COR, R2 = H)

cerebrosides (R 1 = COR, R2 = sugar residue)

– +
sphingomyelin (R 1 = COR, R2 = PO3CH2CH2NMe3)

Figure 6. Structures of sphingolipids.

Alternatively the free hydroxyl group is converted to an appropriate

phosphate ester to produce a phospholipid. Dietary triacylglycerols can be
hydrolysed to 2-monoacyl-sn-glycerols and then reacylated to diacylglycerols
and triacylglycerols.

Fattorusso, E. et al. (1997) Prog. Chem. Org. Nat. Prod., 72, 215 (rev, glycolipids)
Gunstone, F.D. et al. (1994) The Lipid Handbook, 2nd edn, Chapman & Hall, London.
Gunstone, F.D. (1996) Fatty Acid and Lipid Chemistry, Blackie, London.
Jie, M.S.F.L.K. et al. (1997) Nat. Prod. Rep., 14, 163 (rev).

28
Polyketides (VC)
Fungi have the ability to produce a very wide range of structural types of
metabolite which are derived from a poly-β-ketomethylene chain. This chain is
formed by condensation of an acetyl unit (or other acyl unit) with malonyl or
methylmalonyl units, with concomitant decarboxylation as in fatty acid
biosynthesis but without the reduction of the intermediate β-dicarbonyl system.
The resulting polyketide chain can take part in internal aldol-type condensations
to give aromatic systems characterised by an alternating oxygenation pattern.
Alternatively reduction or partial reduction of the carbonyls during biosynthesis
can give rise to nonaromatic metabolites. One method of classifying polyketides
is by the number of acetate (or propionate) units in a metabolite; however, this
has the disadvantage of separating structurally similar types. The vast array of
polyketides is treated in DNP according to a mixture of structural, biosynthetic
and functional criteria. The advantage of this approach is that related
compounds are listed together. Aromatic polyketides are listed under the
appropriate aromatic grouping.

Herbert, R.B. (1989) The Biosynthesis of Secondary Metabolites, 2nd edn, Chapman &
Hall, London.
O’Hagan, D. (1991) The Polyketide Metabolites, Ellis Horwood, New York.
O’Hagan, D. (1992) Nat. Prod. Rep., 9, 447.
O’Hagan, D. (1995) Nat. Prod. Rep., 9, 447.
Simpson, T.J. (1991) Nat. Prod. Rep., 12, 1.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Linear polyketides (VC0050)

This section contains a small number of polyketides that do not contain
carbocyclic or macrolide ring systems.

Marine halogenated acetogenins (VC0070)

Marine metabolites include a series of halogenated polyketides particularly from
red algae (Laurencia spp.). The metabolites contain, along with bromine and
chlorine substituents, oxygen heterocycles, acetylenes and allenes. A typical
example is Bermudenynol.
Cl

H Cl

Br O
OH
Bermudenynol

Faulkner, D.J. (1996) Nat. Prod. Rep., 13, 75.

Annonaceae acetogenins (VC0080)

The Annonaceae are a large family of tropical and subtropical trees. Several
species contain compounds of apparent polyketide origin typified by the first
example of this class, Uvaricin. They contain from 35 to 38 carbons, one, two
or less commonly three tetrahydrofuran rings, a γ-lactone and various other
oxygen functions and are characterised by a three carbon unit joined onto a long
aliphatic chain. The determination of the stereochemistry of this group is often
very difficult since they are generally waxy, amorphous compounds unsuitable
for X-ray analysis.

29
 OH
H O

O
O
H
H
O

H
OAc
Uvaricin

Cavé, A. et al. (1993) Recent Adv. Phytochem, 27, 167

Cavé, A. (1997) Progr. Chem. Org. Nat. Prod, 70, 81
Figadere, B. et al. (1996) Stand. Nat. Prod. Chem., 18, 193 (rev, synth).
Gu, Z.M. et al. (1995) Recent Adv. Phytochem. 29, 249
Gu, Z.M. et al. (1997) J. Nat. Prod., 60, 242 (chromatog, ms)
Rupprecht, J.K. et al. (1990) J. Nat. Prod., 53, 237.
Zafra-Polo, M.C. et al. (1996) Phytochemistry, 42, 253.
Zeng, L. et al. (1996) Nat. Prod. Rep., 13, 275.

Macrolides and lactone polyketides (VC0100, VC0150)

Macrolide antibiotics are metabolites of Streptomyces and Micromonospora spp.
Many antibiotics classified as macrolides have been reported for which full
structures are not described. Structurally, macrolides are a class of complex
glycosidic lactones; the aglycone is normally a 12–16 membered macrocyclic
ring and one to three neutral or aminosugar residues are linked to the aglycone
via ether linkages. Many of the aglycones have also been isolated from the
fermentation broths, often from mutant strains, but these are usually devoid of
biological activity. Erythromycin is a typical macrolide antibiotic.
O
19

HO OH
22
OH
5
O
O CH3
15 1 O
O 1′
O NMe2

HO O OH
CH3 1″
OMe
3″
CH3
Erythromycin

The related milbemycins and avermectins are a group of 16-membered

macrocyclic lactones that possess an oxygen heterocyclic ring fused to the
lactones.

H
O O O H O
HO O
O
CH3 CH3

OMe OMe H
O O
OH H

O
H
OMe
Avermectin A1a

30
Blizzard, T. et al. (1990) Recent Progr. Chem. Synth. Antibiot., 65 (synth).
Davies, H.G. et al. (1986) Nat. Prod. Rep., 3, 87 (Avermectins, Milbemycins).
Davies, H.G. et al. (1991) Chem. Soc. Rev., 20, 211; 271.
Fukagawa, Y. et al. (1988) Life Sci. Rep., 6, 267.
Kornis, G.I. et al. (1991) ACS Sympos. Ser. 443 (Avermectins, Milbemycins).
Nakata, M. et al. (1993) in Studies in Natural Product Chemistry, Vol. 12, (ed. Atta-ur-
Rahman), Amsterdam, Elsevier, pp. 35 (synth).
Neuzil, J. et al. (1986) Folia Microbiol. (Prague), 31, 402 (biosynth).
O’Hagan, D. (1989) Nat. Prod. Rep. 6, 205 (biosynth).
Omura, S. (1984) Macrolide Antibiotics, Chemistry, Biology and Practice, Academic
Press, London (general).
Omura, S. (1986) in Biotechnology, Vol. 4, (ed. H. Page), VCH, Weinheim, pp. 359
(general).
Paterson, I. et al. (1985) Tetrahedron, 41, 3569 (synth).
Seno, E.T. et al. (1986) in The Bacteria, Vol IX, (eds S.W. Queener et al.), Academic
Press, Orlando, pp. 231 (biosynth).
Tatsuta, K. (1990) Recent Prog. Chem. Synth. Antibiot., 1 (synth).

Ansamycins and related polyketides (VC0200)

Ansamycins are benzenoid or naphthalenoid aromatic compounds in which non-
adjacent positions are bridged by an aliphatic chain to form a cyclic structure.
One of the aliphatic-aromatic junctions is always an amide bond. They are
produced by Streptomyces, Nocardia and Micromonospora spp. and have also
been isolated from plant sources; although for the latter, the involvement of
microorganisms has not been ruled out.
The natural ansamycins may be subdivided according to the nature of the
aromatic moiety and the length of the aliphatic chain. The major group contains
a naphthalenoid moiety and a 17 carbon aliphatic chain. Rifamycin is a typical
member of this group. The differences in structure are not merely of chemical
interest but indicate a profound difference in biological activity. Members of
this group show selective antibacterial activity and inhibit RNA polymerase.
The benzenoid ansamycins with a 15-C chain include the Ansamitocins and the
related Maytansine; these compounds show pronounced antitumour activity.

HO

AcO OH O
OH OH NH
MeO
H3C

O OH
O
O
Rifamycin

Antosz, F.J. (1978) in Kirk-Othmer Encyclopedia of Chemical Technology (eds M.

Grayson et al.) Wiley, NY, 2, 852 (isol).
Crandall, L.W. et al. (1986) in The Bacteria Vol IX (ed. S.W. Queener) Academic Press,
Orlando, pp. 360 (isol).
Isobe, M. (1990) Recent Prog. Chem. Synth. Antibiot., 103 (synth).
Lancini, G. (1983) in Biotechnology, Vol 2, (ed. G. Lancini) VCH, Weinheim, Ger., pp.
231 (biosynth).
Lancini, G. (1986) in Biotechnology, Vol 4 (ed. H. Page) VCH, Weinheim, Ger., 431.
O’Hagan, D. (1989) Nat. Prod. Rep., 6, 205.
Reider, P.J. et al. (1984) in The Alkaloids (ed. R. Brossi et al.) Academic Press, 23, 71.
Rickards, R.W. et al. (1991) Stud. Nat. Prod. Chem., 9, 431.
Smith, C.R. et al. (1984) in Alkaloids, Chemical and Biological Perspectives (ed. S.W.
Pelletier) Wiley, New York. 2, 149.
Traxler, P. et al. (1982) J. Antibiot., 35, 1361 (biosynth).

31
Polyenes (VC0300)
The group of antibiotics known collectively as polyenes is characterised by a
large lactone ring (20–44 membered) containing a series of conjugated double
bonds. This leads to the sub-division of the group into trienes, tetraenes etc. The
macrolide ring is often linked by a hydroxyl group to an aminosugar unit and
may have an aliphatic side chain possibly terminating with an aromatic residue.
Streptomyces are the usual producing organisms, and to date over 200
polyenes have been claimed. However, only some of these have established
structures. One reason for the paucity of structural information is that they are
often mixtures of closely related compounds. The advent of HPLC has enabled
better separation to be obtained and has indicated that many polyenes previously
considered to be defined were in fact mixtures of the same components but in
different proportions.
The macrolide ring is probably derived from acetate and propionate,
otherwise little is known about their detailed mechanism of biosynthesis.
Nystatin is a typical polyene antibiotic showing antifungal activity.
OH
COOH
OH OH OH OH
O
HO
OH
O O O
CH3
O
HO NH2OH
HO

Nystatin A1

Beau, J.M. (1990) Recent Prog. Chem. Synth. Antibiot., 135 (synth).
Bolard, J. (1986) Biochim. Biophys. Acta., 864, 257 (props).
Crandall, L.W. et al. (1986) in The Bacteria, Vol IX (ed. S.W. Queener) Academic
Press, Orlando.
Omura, S. (1984) Macrolide Antibiotics, Chemistry, Biology and Practice, Academic
Press, London.
Rinehart, K.L. (1983) Biotechnology, 1, 581 (ms).
Rychnovsky, S.D. (1990) Acta Pharm. Nord., 2, 155.
Simpson, T.J. (1985) Nat. Prod. Rep., 2, 321 (biosynth).
Thomas, A.H. (1986) J. Antimicrob. Chemother., 17, 269 (action).

Linear tetracyclines (VC0400)

The tetracyclines, which contain a polyhydronaphthacene nucleus, form a small
but very important group of antibiotics. Many of the Streptomyces metabolites
have been used clinically since their discovery in the late 1940s. They are active
against gram-positive and gram-negative bacteria, spirochaetes, mycoplasmas
and rickettsiae. In addition they display significant amoebicidal activity and
have efficacy in some diseases caused by large viruses. They have veterinary
applications in promoting growth and feed efficiency. They are second to the β-
lactam group in terms of clinical use and exhibit low toxicity and good oral
absorption. Their mode of action is by the inhibition of protein biosynthesis.
OH
H3C NMe2
H H
6 5 4 OH
10 12 1 CONH2
OH HO
O O
OH
Tetracycline

32
 The biochemistry of tetracycline production has been extensively studied
using mutant strains and cell-free systems to identify a variety of intermediates.
Biosynthetically tetracycline antibiotics are derived from oligoketides.

Aszalos, A. (1985) Chromatographia, 20, 313 (hplc).

Hlavka, J.J. et al. (1985) The Tetracyclines, Handbook of Experimental Pharmacology,
Springer, Heidelberg, pp. 78.
Krohn, K. et al. (1989) Prog. Chem. Org. Nat. Prod., 55, 37.
Mitscher, L.A. (1978) The Chemistry of the Tetracycline Antibiotics, Marcel Dekker,
New York.
Mooibroek, S. et al. (1987) Can. J. Chem., 65, 357 (cmr, bibl).
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Angucyclines (VC0450)
The angucycline antibiotics are related to the tetracyclines but they have an
angular arrangement of the tetracyclic ring system as in Urdamycin A.
Angucyclinones are defined as natural products with a benz[a]anthracene
nucleus but no hydrolysable sugar moieties whereas the term angucycline
includes those with hydrolysable sugars.
O O
CH3
HO O
O OH

CH3 OH
O OH
O
HO O
O
CH3 CH3
O O
OH
HO
Urdamycin A

Rohr, J. et al. (1992) Nat. Prod. Rep., 9, 103.

Polyether antibiotics (VC0500)

The majority of polyethers are characterised by a linear series of tetrahydrofuran
and tetrahydropyran residues, frequently linked by spiroketal systems. These
compounds always terminate with a carboxylic acid residue or a simple ester
function thereof. Some polyethers also carry a sugar unit linked to a hydroxy
group on one of the tetrahydropyran rings. The most common sugar residue is
4-O-methylamicetose.
More than 1000 polyether antibiotics have been isolated so far, mostly as
metabolites of Streptomyces spp., although some Streptoverticillium,
Actinomadura, Nocardia and Dactylosporangium spp. are also reported to
produce them. Polyethers are generally produced as a series of closely related
compounds e.g. the major component may possess methyl substituents on each
of the cyclic ether units, but in addition small amounts of ethyl homologues may
also be present.
Chemical subdivision is based on the number of spiroketal functionalities,
and the presence or absence of a sugar residue.
Polyethers possess the ability to bind and transport certain ions, and each
antibiotic has its own ion specificity. For this reason they are important
biochemical tools in studying the role of cations in biological systems. The
antibiotics show a wide range of activities, being active against gram-positive
organisms and mycobacteria, fungi and yeasts, but because of their toxicity,

33
these properties have found little application. Their uses to date are mainly as
feed additives.
Biosynthetically, the polyethers are polyketide in origin. The major building
blocks are acetate, propanoate, and butyrate. There is evidence to suggest the
intermediacy of an epoxide in the formation of the tetrahydrofuran and
tetrahydropyran systems. Monensin A is a typical polyether antibiotic.

HO
CH2OH
O O O H H O OH
O H H
H

COOH
MeO
Monensin A

Berdy, J. (1986) in Biotechnology, Vol 4, (ed. H. Page) VCH, Weinheim, Ger., pp. 494.
Crandall, L.W. et al. (1986) in The Bacteria, Vol IX (ed. S.W. Queener et al.) Academic
Press, Orlando, pp. 385.
Denyer, S.P. et al. (1983) Antibiotics, Society for Applied Bacteriology, Washington, 77.
Dutton, C.J. et al. (1995) Nat. Prod. Rep., 12, 165.
Robinson, J.A. (1991) Prog. Chem. Org. Nat. Prod., 58, 1.
Siegel, M.M. et al. (1987) Biomed. Environ. Mass Spectrom., 14, 29 (ms).
Westley, J.W. (ed.) (1982) Polyether Antibiotics, Marcel Dekker, NY, (2 vols).
Westley, J.W. (1986) J. Nat. Prod., 49, 35 (biosynth).
Wieranga, W. (1981) in Total Synthesis of Natural Products (ed. J. Ap’Simon) Wiley,
New York.
Yonemitsu, O. et al. (1990) Recent Prog. Chem. Synth. Antibiot., 447 (synth).

Aflatoxins and related substances (VC0600)

Structurally, aflatoxins consist of a hydrogenated difurano-moiety fused to a
substituted coumarin. The naturally occurring aflatoxins are acutely toxic and
extremely carcinogenic compounds produced by Aspergillus spp. Metabolism of
these compounds by microbial and animal species or chemical transformation
leads to a number of equally potent aflatoxin derivatives. Toxic effects centre
primarily on the liver.
The formation of the principal toxin, Aflatoxin B1, has been studied in
considerable detail. The results are consistent with a pathway from a single
decaketide chain via a series of intermediates e.g. Averufin and
Sterigmatocystin. The other aflatoxins are formed from Aflatoxin B1.

O O
O
H

O
H O OMe

Aflatoxin B1

Heathcote, J.G. et al. (1978) Aflatoxins, Chemical and Biological Aspects, Elsevier,
Amsterdam.
Lacey, J. (1987) Trichothecenes and other Mycotoxins, Wiley, New York.
Simpson, T.J. (1984) Nat. Prod. Rep., 1, 287 (biosynth).
Steyn, P.S. et al. (1980) in Biosynthesis of Mycotoxins, Academic Press, New York
(biosynth).
Steyn, P.S. et al. (eds) (1986) Mycotoxins and Phycotoxins, Elsevier, Amsterdam.

34
 Carbohydrates (VE)
This is an abbreviated account dealing only with aspects of carbohydrate
chemistry relevant to natural products. For a fuller coverage including synthetic
carbohydrates, see the companion disc Dictionary of Carbohydrates on CD-
ROM.
Carbohydrates comprise a family of polyhydroxy aldehydes, ketones and
acids, together with linear and cyclic polyols. They are diverse because they
exist as a wide range of stereoisomers.
These compounds are the most abundant and widespread organic substances
in nature and are essential constituents of all living matter. They are the most
important (in terms of volume and availability) of the non-nitrogenous

CHO CHO CHO CHO CHO CHO

H C OH HO C H H C OH HO C H H C OH HO C H
H C OH HO C H HO C H HO C H HO C H H C OH
HO C H HO C H HO C H H C OH H C OH H C OH
H C OH H C OH H C OH H C OH H C OH H C OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D-glucose, Hexitol; D-talose, Hexitol; D-galactose, Hexitol; D-mannose, Hexitol; D-glactose, Hexitol; D-altrose,
D-gulitol (– L- D-talitol galactitol D-mannitol D-gluctiol Hexitol;
glucitol) ( meso-) D-altritol,
(≡D-talitol)

CHO CHO

HO C H CHO CHO CHO CHO H C OH

H C OH H C OH HO C H HO C H H C OH H C OH
HO C H HO C H HO C H H C OH H C OH H C OH
H C OH H C OH H C OH H C OH H C OH H C OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

D-idose, Hexitol; D-xylose D-lyxose, D-arabinose D-ribose D-allose,

D-iditol Pentitol; xylitol Pentitol; D-lyxitol Pentitol; D-Arabinitol Pentitol; ribitol Hexitol; allitol
( meso-) ( ≡D-lyxitol) ( meso-) ( meso-)

CHO CHO

HO C H H C OH
H C OH H C OH

CH2OH CH2OH

D-threose, Tetrol; D-threitol D-erythrose, Tetrol; erythritol

( meso-)

CHO

H C OH

CH2OH

D(R)-glyceraldehyde
Triol; glycerol

Figure 7. The fundamental aldoses, their corresponding alditols and their notional
relationships to glyceraldehyde, as illustrated for sugars of the D-series.

35
 constituents of the chiral pool and are extremely important in chiral synthesis.
Of the 36 possible stereoisomeric pentoses, pentuloses, hexoses and hexuloses
only D-glucose, D-fructose, D-galactose, D-mannose and L-arabinose occur
naturally in the free state, but only the first two are found in significant amounts.
Photosynthesis is the means by which plants produce sugars from carbon
dioxide and water. In brief, it occurs by carbon dioxide being transferred to D-
erythro-pentulose-1,5-diphosphate to give, via an unstable β-keto-6-carbon acid,
two molecules of D-glyceric acid-3-phosphate, from which hexoses, for
example, D-fructose 1,6-diphosphate and D-glucose 1-phosphate can be formed.
Animals on the other hand use the reverse of the glycolysis metabolic pathway
to produce glucose from proteins and fats utilising phosphoenolpyruvate as an
intermediate. Most of the routes used by nature to interconvert sugars occur by
way of enzymic reactions on nucleoside diphosphate sugars, particularly
Uridine diphosphate glucose (UDPG) which gives D-galactose on
epimerization at C-4, D-glucuronic acid by oxidation at C-6 and D-xylose by
decarboxylation of this acid. Deoxygenation at C-6 and configuration changes at
C-4 and C-5 give L-rhamnose and by similar means the commonly occurring D-
sugars may be transformed into members of the L-series.

Fundamental aldoses and ketoses (VE0100–VE2200)

Figures 7, 8 and 9 illustrate the derivation of the (natural and non-natural)
fundamental monosaccharides by the notional chain-lengthening process from
their C3 parents giving rise to sugars of the D- or L-series (illustrated here for D-
sugars).
In DNP, the cyclic forms of the sugars are normally illustrated as Haworth
formulae as shown in Figure 8. Wherever possible, the sugar components of
complex molecules such as antibiotics are shown in the Dictionary in the
standard Haworth orientation so that rapid configurational comparison with

CH2OH CHO

HO C H H C OH
CH2OH
OH HO C H OH
H
CHO H CHO
OH H H C OH OH H
H HO
H C OH
H OH H OH
CH2OH
aldehydo – D-glucose

CH2OH CH2OH
HO C H HO C H
CH2OH CH2OH
O O OH O O OH
OH OH OH OH
OH HO OH HO
OH OH OH OH
α- D-glucofuranose β- D-glucofuranose α- D-glucopyranose β- D-glucopyranose
(Haworth)

HOH2C
O HOH2C
HO OH O
HO OH
HO
HO OH OH
(Mills) (Chair)

Figure 8. Anomerism and ring formation in a simple aldose as exemplified by D-glucose.

36
 COCH2OH COCH2OH COCH2OH COCH2OH

H C H H C OH HO C H H C OH
HO C H HO C H H C OH H C OH
H C OH H C OH H C OH H C OH

CH2OH CH2OH CH2OH CH2OH

D-lyxohexulose D-xylohexulose D-arabinohexulose D-ribohexulose

(tagatose) (sorbose) (fructose) (psicose, allulose)

COCH2OH COCH2OH

HO C H H C OH
H C OH H C OH

CH2OH CH2OH
D-threopentulose D-erythropentulose
(xylulose, lyxulose) (ribulose, adonose)

COCH2OH

H C OH

CH2OH

D-glycerotetrulose
(erythrulose, threulose)

CHO

H C OH

CH2OH

D(R)-glyceraldehyde

Figure 9. The fundamental ketoses and their notional relationships to glyceraldehyde,

illustrated for sugars of the D-series.

other related structures can be made. Alternative representations for β-D-

glucopyranose are shown in Figure 8 according to the planar ring (Mills
formula) and chair conventions which are often encountered. The latter should
be used with caution since it has implications of conformational preference
which may not correspond to reality in all cases.
In the Type of Compound index the simple sugars documented in DNP are
classified into their various stereoisomeric subgroups.
Higher sugars having more than six carbon atoms, some of which occur
naturally, are named using two prefixes, one defining the relative configuration
at the last four carbon atoms in the chain (C-2 to C-5 in a hexose), and the
other, which appears first in the name, defining the configuration at the
remaining chiral centre(s).

37
 CHO

H C OH
D-gluco
HO C H
H C OH
H C OH
D-glycero
H C OH
CH2OH
D-glycero-D-gluco-heptose

Modified aldoses and ketoses (VE2600–VE8400)

The number of natural sugars increases when modified forms of these 36
fundamental sugars are considered. Thus in addition to the common occurrence
of combined forms of the five sugars mentioned above, D-allose, D-talose, D-
arabinose, D-ribose, D-xylose, L-lyxose, D-psicose, L-sorbose and D-tagatose are
also found as their derivatives in varying quantities. It is rather surprising that
the vast number of naturally occurring carbohydrate compounds are derived
from so few sugars in this pool. The shortfall is made up by the occurrence of
so called modified sugars such as deoxy-, amino-, thio-, branched chain, and
higher sugars in addition to various alditols, cyclitols and sugar acids.
Bacteria contain several sugars that are unique to their constitution. Muramic
acid, glycosidically linked to N-Acetylglucosamine, is the disaccharide
repeating unit that forms the peptidoglycan of gram-negative bacterial cell
walls. Several rare deoxy-sugars such as Paratose and Tyvelose are components
of the ‘antigenic’ outer cell wall and these inner and outer regions are linked
through a unique ketodeoxyoctulosonic acid (Kdo). In gram-positive bacteria,
teichoic acids, which are large polymers of the phosphates of D-ribitol or
glycerol, form up to 50% of the cell wall.
Bacterially-produced antibiotics are a rich source of rarer sugars. For
example, the Neomycins, Kanamycins and Paromomycins contain a variety of
amino-sugars. Streptomycin also contains a branched-chain sugar and the
anthracycline, Daunomycin, possesses a dideoxyamino-sugar. Nojirimycin, the
α-glucosidase inhibitor, is 5-amino-5-deoxyglucose and the enediyne antitumor
antibiotic, Calicheamicin, has 4,6-dideoxy-4-thio-ribo-hexose as part of its
carbohydrate structure.
Replacement of a hydroxyl hydrogen, other than at the anomeric position by
an alkyl or aryl group, gives an ether named as an O-substituted sugar (e.g. 3-O-
methylglucose). This, however, is not the case when the anomeric hydroxyl is
involved. The product is then named as a glycoside when the aglycone is
obtained from a relatively simple alcohol (e.g. methyl β-D-glucopyranoside not
1-O-methyl-β-D-glucose). For more complicated aglycones the prefixes
glycosyloxy or O-glycosyl can be used. For example 3α- (β-D-
glucopyranosyloxy)-5-β-pregnan-20-ol can also be named as 3-O-(-β-D-
glucopyranosyl)-5β-pregnane-3α, 20-diol. The latter system is often used to
name oligosaccharides (see later). However, when the anomeric hydroxyl is
esterified the product can be referred to as a 1-O-substituted sugar or
alternatively, the glycosyl prefix can be used (e.g. 1-O-acetyl-α-D-
glucopyranose or α-D-glucopyranosyl acetate); for esters of phosphoric acid 1-
phospho-α-D-glucopyranose or α-D-glucopyranosyl phosphate may be used, but
D-glucose 1-phosphate is in common use.
N-Glycosides can be conveniently named glycosylamines. Thus, for example,
N4-(2-acetamido-2-deoxy-β-D-glucopyranosyl)asparagine can also be called 2-
acetamido-N1-(β-aspartyl)-2-deoxy-β-D-glucopyranosylamine.

38
 In many natural products hydroxy groups other than at the anomeric centre of
the sugar are replaced by a thiol-group, an amino-group or a hydrogen atom.
Compounds arising from these changes are named respectively as thio-sugars
(e.g. 3-thioglucose), aminodeoxysugars (e.g. 3-amino-3-deoxyglucose) and
deoxy sugars but in this case the configuration of the remaining asymmetric
carbons must be described with a prefix (e.g. 3-deoxy-ribo-hexose not 3-
deoxyglucose).

Branched-chain sugars (VE7200)

Carbon chain branching in sugars can arise biogenetically in two ways; either
C-bonded hydrogen atoms are replaced as in HO-H→ HO-R in which case the
products are C-substituted derivatives of the normal straight-chain compounds
and are classified as members of the ‘dehydro’ group, or else hydroxyl functions
are replaced as in HO-H→ R-H. In the naming of the latter class the ‘deoxy’
prefix is included to denote the absence of the hydroxyl substituent at the
branching carbon atom, and members can be described as belonging to the
‘deoxy’ group of branched chain sugars. (e.g. 3-C-methyl-D-glucose and 3-
deoxy-3-C-methyl-D-glucose are the respective names of compounds obtained
by replacing in glucose either the hydrogen at C-3 or the hydroxyl at C-3 by
methyl).

Carbohydrate acids VE7900, VE8000, VE8100, VE8200)

The following four types of carbohydrate acids occur in nature for which named
examples are given for compounds derived from glucose: aldonic acids
(VE7900) (D-Gluconic acid) which are formed when the aldehydic function in
an aldose is oxidized; aldaric acids (VE8100) (D-Glucaric acid) which are
dicarboxylic acids formed by oxidation of the aldehydic groups and
hydroxymethyl groups in aldoses; uronic acids (VE8000) (D-Glucuronic acid)
and ketoaldonic acids (VE8200) (D-arabino-Hex-2-ulosonic acid) which are
formed by oxidation of the hydroxymethyl groups in aldoses and ketoses
respectively.
Glycopyranosides (e.g. methyl) and esters (e.g. benzyl) of the last two acids
are named in the following way: benzyl(methyl-α-D-glucopyranosid)uronate for
the former and benzyl(methyl α-D-arabino-hex-2-ulopyranosid)onate for the
latter.

Alditols (VE8600–VE8900)
The polyols obtained by reduction of the aldehyde function of an alditol (or the
keto function of a ketol) are known as alditols. An example is Mannitol. They
are named by a straightforward extension of the rules used for aldoses. The
alditol corresponding to a chiral sugar may be meso-, e.g. Galactitol.

Cyclitols (VE9000)
The polyhydroxycycloalkanes, known as cyclitols, are a group of natural
products closely related to the carbohydrates proper, of which the most
important are the inositols (1,2,3,4,5,6-cyclohexanehexols). Trivial names are
often used but systematic rules have been introduced to assign configurations at
each enumerated ring carbon atom and this requires the application of a
recommended numbering convention. Further information on the various
descriptions of stereochemistry for these compounds can be obtained by the
inspection of the individual Dictionary entries. It should be noted that some
meso-isomers in the series can have optically active derivatives.

39
 myo-Inositol is the most abundant cyclitol, occurring both free and as its
derivatives. Its hexaphosphate is phytic acid and occurs in large amounts in
grain. myo-Inositol and its derivatives are universally present in cells and the
1,4,5-trisphosphate plays a vital role as a secondary messenger, which mediates
mobilization of intercellular calcium ions.

Anderson, L. (1972) in The Carbohydrates, (ed. W. Pigman and D. Horton) Academic

Press, IA, 519.
Angyal, S.J. and Anderson, L. (1959) Adv. Carbohydr. Chem., 14, 135.
Posternak, Th. (1965) The Cyclitols, Holden-Day, San Francisco.
Reitz, A.B. (1991) Inositol Phosphates and Derivatives, ACS Symposium Series,
Washington, DC.

Disaccharides (VE9200)
These are formed by sugars combining with each other by way of glycosidic
links. If the anomeric position of a sugar is attached to the anomeric oxygen of
another, then non-reducing disaccharides such as the glucosylglucoside,
Trehalose, or the fructosyl-glucoside, Sucrose, are formed. The latter
compound is widespread, occurring in most plants. It constitutes a significant
part of man’s diet in Europe and the USA, being produced in pure form on a
larger scale than any other monomeric organic compound. If the glycosidic
bond in a disaccharide is to a non-anomeric hydroxyl of the second sugar, then
so-called reducing disaccharides are formed, Maltose and Lactose being typical
examples.

Oligosaccharides and polysaccharides (VE9300, VE9400)

These are obtained by repetition of the glycosylation process on reducing
disaccharides. The former are most often found as glycosides in, for example,
plants, antibiotics and some glycoproteins. Polysaccharides are the most
abundant form of carbohydrates. Cellulose, for example, is an industrial raw
material with world consumption approaching 109 tons p.a. It is the principal
constituent of plant cell walls providing their structural strength. Starch and
Glycogen are found preponderantly in plants and animals respectively where
they serve as energy reserves. Whereas glucose is the building unit for the
previous three polymers, Chitin, which is found in the shells of arthropods, is a
polymer of 2-acetamido-2-deoxyglucose.
Oligosaccharides with a free hemiacetal group are named as
glycosylglycosylglycoses as illustrated by Cellotriose, for example, which is β-
D-glucopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 4)-D-glucose (Chemical
Abstracts inserts O-locants as in O-β-D-glucopyranosyl-(1 → 4)-O-β-D-
glucopyranosyl-D-glucose). Branched oligosaccharides use square brackets in
the name to designate branching, e.g. α-D-glucopyranosyl-(1 → 4)-[α-D-
glucopyranosyl (1 → 6)]-D-glucopyranose. Polysaccharides use an extended
form of this nomenclature.
HOH2C
O
HOH2C OH OH
O O
HOH2C OH OH
O O
OH OH
HO
OH
Cellotriose

40
 Glycosidic bonds in naturally occurring oligosaccharides and glycosides are
formed in natural glycosylations which take place primarily by way of the
nucleoside diphosphate sugars as follows:
nucleoside DP sugar + ROH → sugar OR + nucleoside DPH
Disaccharides or their phosphates are produced when ROH is a sugar or a
sugar phosphate. Polysaccharide biosynthesis is basically similar but requires an
oligomer primer as an acceptor; glycogen synthesis follows the course:
primer + UDPG → Gα-primer + UDP
there being one enzyme present which catalyses the formation of 1,4-bonds and
another responsible for glycosylations at position 6. The biosynthesis of
cellulose and other polysaccharides is basically similar, UDP being the
nucleoside diphosphate used predominantly. However, starch synthesis depends
rather on adenosine diphosphate.
Carbohydrates are important components of a variety of significant
biopolymers, the most obvious being DNA and RNA which contain 2-Deoxy-D-
ribose and D-Ribose respectively. Glycoproteins and glycolipids (described
elsewhere) are another important group, although the carbohydrates are usually
present as oligomers, comprising sugars drawn from the following: 2-
acetamido-2-deoxy-D-glucose, 2-acetamido-2-deoxy-D-galactose, D-mannose, D-
galactose, sialic acid and L-fucose, which are glycosidically attached to the
protein. They are widely distributed in all living organisms, occurring bound to
cell membranes and in a free soluble form. Their role has only recently been
appreciated as it becomes evident that they serve as recognition sites for a
variety of intra- and intermolecular communication events. They function as
specific binding sites for enzymes, hormones, soluble toxins, bacteria, and
viruses. They are also implicated in cell-cell recognition and interaction, such as
cell adhesion which is particularly important in inflammatory diseases. They
play a role in the development of normal cells and metastasis in cancer cells.
The structural basis for blood ABO(H) and Lewis group antigenicities resides in
the oligosaccharide portions of blood cell glycolipids and the associated
secreted glycoproteins.

Glycosaminoglycans (included in VE9400)

Mucopolysaccharides are another group of high molecular weight sugars usually
formed by polymerization of a disaccharide. Dermatan sulfate, for example,
contains L-iduronic acid and D-galactosamine 4-sulfate as the repeating unit.
Others in this group are Chondroitin, Keratan sulfate, Hyaluronic acid and
Heparin which are found in body fluids and associated with connective tissue.
Mucopolysaccharidosis comprises several rare and fatal metabolic diseases,
among them being Hurler’s syndrome and Hunter’s disease, in which some of
these compounds accumulate to abnormal levels in the tissues of affected
individuals.

Plant glycosides
Glycosides of many different aglycones are ubiquitous in the plant kingdom.
Many are formed from phenols, polyphenols, steroidal and terpenoidal alcohols
by glycosidic attachment to sugars. In a majority of cases D-glucose is present
but L-rhamnose, D- and L- fucose and L-arabinose occur quite frequently. Of the
pentoses, L-arabinose is more common than D-xylose and the sugars often occur
as oligosaccharides. For example, Digitonin and Digitoxin from Digitalis
contain respectively a branched heteropentasaccharide, comprising two glucose

41
and two galactose molecules and xylose, and a linear homotrisaccharide of 2,6-
dideoxy-β-D-ribo-hexose.
Tannins (see separate section below) are a special case of plant glycoside.
In general, the plant glycosides are so numerous that their sugar components
are not reported as such in the carbohydrate section of the Type of Compound
Index, except for a few special classes described below.

Casu, B. (1985) Adv. Carbohydr. Chem. Biochem., 43, 51.

Collins, P.M. (1997) Dictionary of Carbohydrates, Chapman & Hall.
Courtois, J.E. and Percheron, F. (1970) in The Carbohydrates, (eds W. Pigman and D.
Horton) Academic Press, II, 213.
Hassid, W.Z. (1970) in The Carbohydrates, (eds W. Pigman and D. Horton) Academic
Press, IIA, 301.
Hughes, R.C. (1983) Glycoproteins, Chapman & Hall, London.
Jeanloz, R.W. (1970) in The Carbohydrates, (eds W. Pigman and D. Horton) Academic
Press, IIB, 590.
Lee, M.D. et al. (1991) Acc. Chem. Res., 24, 235.
Lemieux, R.U. (1978) Chem. Soc. Revs., 7, 423.
Lindberg, B. (1990) Adv. Carbohydr. Chem. Biochem., 48, 279.
Mallams, A.K. (1988) in Carbohydrate Chemistry (ed. J.F. Kennedy) Clarendon Press,
Oxford, pp. 73.
Montreuil, J. (1980) Adv. Carbohydr. Chem. Biochem., 37, 157.
Rademacher, T.W. et al. (1988) Ann. Rev. Biochem., 57, 785.
Schmidt, O. Th. (1956) Fortschr. Chem. Org. Naturst., 13, 70.
Sharon, N. and Lis, H. (1993) Sci. Am., 74.
Umezawa, S. (1974) Adv. Carbohydr. Chem. Biochem., 30, 111.
IUPAC/IUBMB Joint Commission on biochemical nomenclature of Carbohydrates,
Pure Appl. Chem., 1996, 68, 1919.

Aminoglycoside antibiotics
Aminoglycosides constitute a large and diverse group of metabolites produced
by both bacteria and Streptomyces. The group covers those antibiotics
containing a highly functionalised cyclohexane aglycone, i.e. cyclitol,
glycosidically linked to amino or neutral sugar residues.
The streptamine cyclitol sub-group are Streptomyces metabolites which have
broad spectrum activity. They find clinical use both as topical and systemic
agents but exhibit varying degrees of oto- and nephrotoxicity thus limiting their
application. In addition many are rendered ineffective by resistant strains
carrying aminoglycoside inactivating enzymes.
The group of aminoglycosides containing inositol and/or monoamino-
cyclitols, which are produced by Streptomyces and Nocardia spp. represent a
much smaller subdivision.
In the Type of Compound Index, the aminoglycoside antibiotics are listed
under one or more structural categories (e.g. cyclitol), but a general
bibliography is given here.

Gambardella, P. et al. (1985) J. Chromatogr., 348, 229 (hplc).

Gero, S.D. et al. (1984) Stud. Org. Chem. (Amsterdam), 17, 79 (synth).
Grisebach, H. (1978) Adv. Carbohydr. Chem. Biochem., 35, 122 (biosynth).
Inchauspe, G. et al. (1985) J. Antibiot., 38, 1526 (hplc).
Okachi, R. et al. (1984) Drugs Pharm. Sci., 22, 329 (biosynth).
Rinehart, K.L. (ed.) (1980) Aminocyclitol Antibiotics, Amer. Chem. Soc.
Schubert, J. et al. (1986) Justus Liebigs Ann. Chem., 2009 (synth).
Umezawa, H. et al. (1982) Handbook of Experimental Pharmacology, Springer, Berlin,
62 (biosynth).
Umezawa, S. (1986) in Biotechnology, Vol 4 (ed. H. Page), VCH, Weinheim, Ger., pp.
309.

42
Whelton, A. et al. (1982) The Aminoglycosides, Marcel Dekker, New York.
Williams, N.R. (ed.) (1986) Carbohydr. Chem., Royal Society of Chemistry, London,
18, 176.

Nucleosides (VE9900)
These are glycosides of purines, pyrimidines and other heterocyclic bases. The
well-known quartet of Adenosine, Guanosine, Cytosine and Thymidine are
fundamental biomolecules essential to life through their participation in the
structure of DNA and RNA. A small number of ‘hypermodified’ nucleosides
such as Wybutosine occur in bacterial nucleic acids.
A more prolific source of different nucleoside structures is the nucleoside
antibiotics which are analogues of the essential purine and pyrimidine
nucleosides. They consist of a sugar linked to a base either via a ring nitrogen or
through a ring C atom (the latter are designated C-nucleosides). Structurally
they are rather diverse but a subclassification is given by Isono (loc. cit.).
Although most of the compounds are Streptomyces metabolites, fungal and
bacterial products have also been identified.
Many nucleosides show interesting antiviral and antitumour properties, and
find wide application as biochemical tools. The commercial importance of
synthetic and semisynthetic compounds has led to a concentration of research
effort on synthetic methods and several good reviews on this subject are
available.
A few nucleotides (nucleoside phosphate conjugates) are also found, e.g.
Agrocin 84.

Brown, E.G. (1991) Methods Plant Biochem., 5, 53.

Buchanan, J.G. (1982) Top. Antibiotic Chem., 6, 229.
Buchanan, J.G. (1983) Prog. Chem. Org. Nat. Prod., 44, 243 (C-nucleosides).
De las Heras, F.G. et al. (1990) Recent Prog. Chem. Synth. Antibiot., 321.
Eckardt, K. (1983) J. Nat. Prod., 46, 544.
Garner, P.P. (1988) Stud. Nat. Prod. Chem., 1, 397 (synth).
Grisebach, H. (1978) Adv. Carbohydr. Chem. Biochem., 35, 122 (biosynth).
Hobbs, J.B. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 259.
Isono, K. (1988) J. Antibiot., 41, 1711 (biosynth, struct).
McCloskey, J.A. (1990) Methods Enzymol., 193, 771 (anal, ms).
Secrist, J.A. et al. (eds) (1989) Nucleosides Nucleotides, 8, parts 5 and 6 (rev).
Suhadolnik, R.J. (1979) Nucleosides as Biological Probes, Wiley, New York.
Suhadolnik, R.J. (1981) Antibiotics (N.Y.), 4, 353 (biosynth).
Townsend, L.B. (1988) Chem. of Nucleosides and Nucleotides Vol. 1, Plenum Press,
New York.
Williams, N.R. (ed.) (1986) Carbohydrate Chemistry, Royal Society of Chemistry,
London, 18, 176, 190.

43
Oxygen heterocycles (VF)
Many simple natural products contain basic oxygen heterocycles – for example
the furan derivative, Furaneol, the pyran-2-one derivative, Triacetic acid lactone
and the 4-pyrone, Kojic acid. Although most of these simple oxygen
heterocyclic compounds can be seen to be derived from polyketides or
carbohydrates, some have unknown biosynthetic origins. The oxygen
heterocycles are listed under the headings: β-Lactones (VF1000), Furans
(VF2000), Butanolides (VF3000), Pyrans (VF4000), Pentanolides (VF5000), 2-
Pyrones (VF6000) and 4-Pyrones (VF7000). Natural products that contain these
substructures in terpenoid, steroid or alkaloid skeletons are not listed here.

O
O OH
OH
HO
CH3 H3C CH2OH
H3C O O O O
Furaneol Triacetic acid lactone Kojic acid

Davies-Coleman, M.T. et al. (1989) Prog. Chem. Org. Nat. Prod., 55, 1.
Dickinson, J.M. (1993) Nat. Prod. Rep., 10, 71.
Ley, S.V. (1991) in Heterocycles in Bioorganic Chemistry, (eds J. Bergman et al.), RSC,
London.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Avenaciolide and glauconic acid groups (VF5100, VF5200)

Separate listings are given for the bislactones related to Avenaciolide and the
dimeric anhydrides related to Glauconic acid.
O

O OH
H H O O

O O O

O O
Avenaciolide Glauconic acid

Spiroketals (VF8000)
There are a number of biologically active spiroketals, clearly of acetate origin,
exemplified by 1,7-Dioxaspiro[5.5]undecane, a sex pheromone of the olive fly
(see also Aliphatic Natural Products above).

O O

1,7-Dioxaspiro[5.5]undecane

44
Simple aromatic natural
products (VG)
Simple benzene derivatives
These may be of terpenoid, polyketide or shikimate origin. Those of terpenoid
origin, such as the aromatic p-menthanes are listed in the terpenoid section.
Since there is a large number of benzenoid compounds they have been
subdivided into simple benzenes (VG0005), simple phenols (VG0010), simple
benzyl alcohols (VG0020), simple benzaldehydes (VG0030), simple aryl
ketones (VG0035), simple benzoic acids (VG0040), phenylacetic acid
derivatives (VG0050) and simple phenylpropanoids (VG0060). Benzoquinones
are listed according to their number of oxygen substituents. (VG0300–VG0330)
with a separate code for prenylated representatives (VG0370).
Fungi are a prolific source of simple benzoquinones which in the main arise
by the polyketide route.

Dewick, P.M. (1995) Nat. Prod. Rep., 12, 101, 579.

Gill, M. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 60.
Herbert, R.B. (1989) The Biosynthesis of Secondary Metabolites, 2nd edn, Chapman &
Hall, London.
Simpson, T.J. (1984) in The Chemistry of Natural Products (ed. R.H. Thomson),
Blackie, Glasgow, pp. 107.
Simpson, T.J. (1991) Nat. Prod. Rep., 8, 573 (biosynth).
Thomson, R.H. (1971) Naturally Occurring Quinones, 2nd edn, Academic Press,
London.
Thomson, R.H. (1987) Naturally Occurring Quinones III, Chapman & Hall, London.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.
Tyman, J.H.P. (1979) Chem. Soc. Rev., 7, 499 (long chain phenols).

Shikimic acid is derived from glucose in plants via the shikimate pathway.
Shikimic acid is the biogenetic precursor of the aromatic amino acids,
Phenylalanine, Tyrosine and Tryptophan. As the shikimate pathway is found
in plants but not in animals there is a great deal of interest in targeting shikimate
pathway enzymes for control of plant growth, particularly after the success of
Glyphosate as a herbicide.

COOH

HO OH
OH
Shikimic acid

The shikimic acid pathway feeds many biosynthetic routes including those
involving p-aminobenzoic acid, anthranilic acid, cinnamic acid and other
phenylpropanoids and hence to many other classes of natural products including
the flavonoids and lignans.

Bentley, R. (1990) Crit. Rev. Biochem. Mol. Biol., 25, 307.

Campbell, M.M. et al. (1993) Synthesis, 165 (synth).
Conn, E.E. et al. (1986) Recent Adv. Phytochem., 20, 1.
Dewick, P.M. (1992) Nat. Prod. Rep., 9, 153 (biosynth).
Floss, H.G. (1979) Recent Adv. Phytochem., 12, 59.
Haslam, E. (1993) Shikimic Acid, Wiley, Chichester.

45
Diphenylmethanes, acylphloroglucinols and benzophenones (VG0450,
VG0460, VG0500–VG0506)
A small number of simple diphenylmethanes occur naturally but there is a
growing number of acylphloroglucinols being identified. Acylphloroglucinol
derivatives may have more than one diphenylmethane linkage and various alkyl
substituents. They are formed by coupling of aromatic units. Other couplings
can lead to benzophenone derivatives. The benzophenones, like the
benzoquinones, are subdivided in the Type of Compound index according to the
number of oxygen substituents.
O O
HO OH

HO OH HO OH

Diphenylmethane Typical acylphloroglucinol

1,1′-Methylenebisbenzene, derivative
9CI
O
OH
COCH3

HO OH
Acetylphoroglucinol Benzophenone
Diphenylmethanone, 9CI

Dibenzofurans, griseofulvins, dibenzopyrans and xanthones (VG0520,

VG0530, VG0535, VG0550–VG0556)
Biogenetically this group of compounds may arise by coupling of aromatic rings
as for Usnic acid or by ring cleavage of polycyclic aromatic compounds. The
xanthones are again listed in subsections according to their number of oxygen
substituents.
OMe
OMe O
9 1 2
8
7 O
6 5 4 3
O MeO O
Cl
Dibenzofuran, 9CI Griseofulvin

2
1 3
4 8 9 1
7 2
10 6 3
9 5 10 4
8
7 6 5 O
O
Dibenzo[b,d]pyran Dibenzo[b,e]pyran
9H-Xanthene, 9CI

O
8 1
7 2
6 3
5 4
O
Xanthone
9H-Xanthen-9-one, 9CI

Afzal, M. et al. (1980) Heterocycles, 14, 1173.

Bennett, G.J. et al. (1989) Phytochemistry, 28, 967.
Sargent, M.V. (1984) Prog. Chem. Org. Nat. Prod., 45, 103.
Sultanbawa, M.U.S. et al. (1980) Tetrahedron, 36, 1465.
Turner, W.V. (1971) Fungal Metabolites, Academic Press, London.

46
Depsides and depsidones; other lichen substances (VG0600–VG0660)
Depsides are esters of polyketide aromatic acids with polyketide phenols such
as Lecanoric acid. Depsidones have an additional ether linkage to form a seven
membered ring as in Colensoic acid. Depsides and depsidones are
predominantly found in lichens, and often carry one or more chlorine
substituents; halogenated depsides and depsidones are indexed separately.
O
O
CH3
CH3 OH
COO
MeO O COOH
HO OH COOH
OH
Lecanoric acid
(Depside) Colensoic acid
(Depsidone)

Sargent, M.V. (1984) Prog. Chem. Org. Nat. Comp., 45, 103.

Diphenyl ethers, biphenyls, dibenzyls and stilbenes (VG1000, VG2000,

VG3000, VG4000–VG5000)
Diphenyl ethers and biphenyls probably arise by radical coupling mechanisms
whereas dibenzyls and stilbene derivatives may be derived from a mixed
shikimate-polyketide pathway. A large number of stilbene derivatives have been
isolated from Morus species.
3 2 2′ 3′
O 4 1 1′
5′ 6′
4′
5 6

Diphenyl ether Biphenyl

Dibenzyl Stilbene

Gorham, J. (1995) Biochemistry of the Stilbenoids, Chapman & Hall.

Nomora, T. (1988) Prog. Chem. Org. Nat. Prod., 53, 87.

Diarylalkyls, terphenyls and the pulvinone group (VG7000, VG7500,

VG7600)
Diarylalkyls having more than four carbons separating the aromatic rings may
be of mixed biogenetic origin. The terphenyls and the pulvinone group are
strictly neolignans (see below) as they arise from two molecules of a
phenylpropanoid.
Ph OH
COOH
O O
Ph
Pulvinic acid

Gill, M. et al. (1987) Prog. Chem. Org. Nat. Prod., 51, 1.

Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

47
Benzofuranoids (VH)
Simple benzofurans (VH1000), benzodifurans (VH2000) and isobenzofurans
(VH3000) (including phthalides) are listed here. Dimeric phthalides are
Diels–Alder adducts belonging to the Angeolide Group (VH3200). 2-
Phenylbenzofurans are probably derived biogenetically from stilbenes.
4 3 5 4 3
5
6 2 6 2
7 1 7 1
8
O O O
Benzofuran Benzodifuran
Benzo[b]furan, 9CI Benzo[1,2-b : 5,4-b′]furan, 9CI

5
4 3 O O
2O
6
7 1 O

O
Isobenzofuran
1(3H)-Isobenzofuranone, 9CI Angeolide

Dean, F.M. (1963) Naturally Occurring Oxygen Ring Compounds, Butterworths,

London.
Livingstone, R. (1973) in Rodd’s Chemistry of Carbon Compounds, Elsevier,
Amsterdam, Vol IVA, Suppl., 1984.

48
Benzopyranoids (VI)
1-Benzopyrans (VI0030)
Historically 1-benzopyrans have been known as chromans, chromanones,
chromones, and 2- and 3-chromenes but in DNP the simpler members are
named systematically. A large number of natural products, of both polyketide
and shikimate derivation, occur naturally. The coumarins are the largest class of
1-benzopyran derivatives. They are found mainly in higher plants. Most natural
coumarins are oxygenated at C-7; Umbelliferone (7-hydroxycoumarin) being
regarded as the structural and biogenetic parent of the more highly oxygenated
coumarins. Prenylation at carbon and oxygen is common in a large number of
coumarins. The prenyl groups found in coumarins exhibit the greatest number of
biogenetic modifications including cyclisation to dihydropyrans, pyrans,
dihydrofurans and furans. In the Type of Compound Index the very numerous
coumarins are subdivided into classes of manageable size according to their
oxygen substitution pattern (VI0100–VI7500), with separate sections for natural
products having additional rings; furo-1-benzopyrans (VI0050) and pyrano-1-
benzopyrans (VI0070).
O
4 5 4
5 3 3
6 6
7 7 1 2
8 1 2 8
O O
Chroman Chromanone
3,4-Dihydro- 2,3-Dihydro-
2H-1-benzopyran, 4H-1-benzopyran-
9CI 4-one, 9CI

O
5 4 5 4
6 3 6 3
7 12 7 12
8 8
O O
Chromone 2-Chromene
4H-1-Benzopyran-4-one, β-Chromene
9CI 4H-1-Benzopyran, 9CI

5 4 5 4
6 3 6 3
7 1 2 7
8 8 1 2
O O O
3-Chromene Coumarin
α-Chromene 2H-1-Benzopyran-2-one,
2H-1-Benzopyran, 9CI 9CI

Ellis, G.P. (ed.) (1977) Chromenes, Chromones and Chromanones, Wiley, New York.
Gill, M. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 65.
Livingstone, R. (1977) in Rodd’s Chemistry of Carbon Compounds, Vol. IVE, Suppl.
1990.
Murray, R.D.H. et al. (1982) The Natural Coumarins, Wiley, Chichester.
Murray, R.D.H. (1991) Prog. Chem. Org. Nat. Prod., 58, 83.
Murray, R.D.H. (1997) Prog. Chem. Org. Nat. Prod., 72, 1.

2-Benzopyrans (VI9600)
Compared to the 1-benzopyrans, the 2-benzopyrans are less common. They are
normally of polyketide origin. The isochromene nucleus is found in fungal

49
metabolites such as Citrinin. Isocoumarins (VI9700) are the largest class of 2-
benzopyran derivatives.

6 5 4 4
3 5 3
6
7 8 2 7 2
1 O 8 1 O

Isochromene O
Isobenzopyran Isocoumarin
1H-2-Benzopyran, 9CI 1H-2-Benzopyran-1-one, 9CI

Hill, R.A. (1986) Prog. Chem. Org. Nat. Prod., 49, 1.

Livingstone, R. (1977) in Rodd’s Chemistry of Carbon Compounds, Vol. IVE, Suppl.
1990.
Murray, R.D.H. (1995) Nat. Prod. Rep., 12, 477.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

50
Flavonoids (VK)
The flavonoids are a large group of natural products which are widespread in
higher plants but also found in some lower plants including algae. The
anthocyanidins are responsible for flower colour in the majority of angiosperms,
but colourless flavonoids are also widespread and abundant. A variety of
biological functions is fulfilled by various members of the series, but many
metabolic and extracellular roles doubtless remain to be discovered.
Flavonoids fall into two major categories according to whether the central
heterocyclic ring is unsaturated or not. When unsaturation is present, as in
anthocyanins, flavones and flavonols, the molecule is planar (occasionally
distorted, e.g. by the substitution of the 2′-hydroxyl group in a 3-O-methyl
flavonol). Saturated flavonoids (flavanones, flavans) have one or more chiral
centres. Optical activity may also be present in flavonoids due to the presence of
glycosidic substituents.
Flavonoids can be classified according to their biosynthetic origin. Some
flavonoid types are both intermediates in biosynthesis as well as end-products,
which can accumulate in plant tissues. These include chalcones (the first formed
C15 structure derived from malonyl coenzyme A and p-coumaryl coenzyme A),
flavanones, flavanon-3-ols and flavan-3,4-diols. Other classes are only known as
end-products of biosynthesis, e.g. anthocyanins, flavones and flavonols. Two
further classes of flavonoid are those in which the 2-phenyl sidechain of
flavonoid isomerises to the 3-position (giving rise to isoflavones and related
isoflavonoids) and then to the 4-position (giving rise to the neoflavonoids).
Isoflavone
c
a d
chalcone flavanone flavone
a e
d
b
aurone flavanon-3-ol flavonol
b

dihydrochalcone flavan-3,4-diol anthocyanidin

f
e
flavan-3-ol proanthocyanidin
f

flavan

Biosynthetic relationship of flavonoids

a = cyclisation, b = bioreduction, c = aryl migration,
d = dehydrogenation, e = hydroxylation,
f = dehydroxylation

Flavonoids may also be classified according to molecular size. While the

majority of flavonoids are monomeric, an increasing number of dimeric and
oligomeric structures are being described. Most biflavonoids are based on
carbon-carbon linking of two similar flavone units, but mixed dimers (e.g.
flavonylflavanones) are known. The highest molecular weight flavonoids are the
oligomeric and polymeric proanthocyanidins, derived biosynthetically from
flavan-3-ols.
Most flavonoids occur naturally associated with sugars in conjugated form
and within any one class may be characterised as monoglycosidic, diglycosidic,
etc. Glycosidic complexity is considerable. There are, for example, over 2,000
glycosides of the flavones and flavonols that have been isolated to date. (There
is a considerable number of glycosides isolated in the course of earlier work
which have only been partially characterised structurally and which may or may
not be identical with fully characterised glycosides isolated later.) Mono-, di-
and trisaccharides may be linked through a phenolic hydroxyl; and one or more

51
such OH groups may carry a sugar substitution. Acylated O-glycosides are
known, where aromatic or aliphatic acids are linked through the 6-hydroxyl of a
glucose moiety. A special group of mainly flavone-based C-glycosides occurs in
plants. Sulfated conjugates are common in the flavone and flavonol series,
where the sulfation may be on a phenolic hydroxyl and/or on an aliphatic
hydroxyl of a glycoside moiety.
A fairly considerable number of C-glycosylated flavonoids occur naturally.
These are readily distinguished from O-glycosyl derivatives by their resistance
to acid hydrolysis. They commonly have one or two sugar residues directly
linked by a carbon-carbon bond at the C-1 of the sugar to the 6- or 8-position of
the flavone nucleus. Thus, the flavone Apigenin can occur with a glucose at C-6
and C-8 (Isovitexin) or at C-8 (Vitexin) or at both C-6 and C-8 (Vicenin 2).
Other apigenin C-glycosides are known where the carbon linked sugar is
arabinose, galactose or xylose or two of these monosaccharides.
C-Glycosides of flavones commonly occur both as such and with further
sugars O-glycosidically linked. These other glycosides readily lose their O-
linked sugar(s) on acid hydrolysis. Such O-glycosidic residues may be attached
either to a hydroxyl of the C-sugar or directly to one of the free phenolic
groups. Acylated C-glycosides have been described, e.g. the 2′′-p-coumarate of
Vitexin. Many flavone C-glycosides are known and they are widely distributed
throughout the plant kingdom. By contrast, C-glycosides of other classes of
flavonoid (e.g. flavonols, flavanones, isoflavones) are of rare occurrence.

Agrawal, P.K. (ed.) (1989) Carbon-13 NMR of Flavonoids, Elsevier, Amsterdam.

Barron, D. et al. (1996) Phytochemistry, 43, 921 (prenylated flavonoids).
Dean, M. (1963) Naturally Occurring Oxygen Ring Compounds, Butterworths, London.
Donnelly, D.M.X. et al. (1995) Nat. Prod. Rep., 12, 321 (isoflavonoids, neoflavonoids).
Ferreira, D. et al. (1996) Nat. Prod. Rep., 13, 411 (proanthocyanins).
Gabor, M. (1986) The Pharmacology of Benzopyrone Derivatives, Akademiai Kiado,
Budapest.
Geissman, T.A. (ed.) (1962) The Chemistry of Flavonoid Compounds, Pergamon Press,
Oxford.
Harborne, J.B. (1967) Comparative Biochemistry of the Flavonoids, Academic Press,
London.
Harborne, J.B. Mabry, T.J. and Mabry, H. (eds) (1975) The Flavonoids, Chapman &
Hall, London.
Harborne, J.B. and Mabry, T.J. (eds) (1982) The Flavonoids: Advances In Research,
Chapman & Hall, London.
Harborne, J.B. (ed.) (1988) The Flavonoids: Advances in Research Since 1980,
Chapman & Hall, London.
Harborne, J.B. (ed.) (1989) Methods in Plant Biochemistry, Volume 1. Plant Phenolics,
Academic Press, London.
Harborne, J.B. (ed.) (1994) The Flavonoids: Advances in Research Since 1986,
Chapman & Hall, London.
Harborne, J.B. et al. (1995) Nat. Prod. Rep., 12, 639 (anthocyanins).

In general there are two parallel systems of nomenclature, one based on trivial
names such as flavan and chalcone as the parent structure and the other based
on systematic chemical names, such as 3,4-Dihydro-2H-1-benzopyran (CA) for
flavan. The latter becomes cumbersome and easy to get wrong in cases of
polysubstitution. There are also two systems of ordering the substituents around
the flavan nucleus: one in which the A-and B-ring substituents precede C-ring
substituents (e.g. 3,5,7, 3′,4′-pentahydroxyflavone); and one in which the
substituents are ordered numerically (e.g. 3,3′, 4′, 5,7-pentahydroxyflavone).
There are additionally two conventions for drawing flavonoid formulae, with the
heterocyclic oxygen at the top and with the heterocyclic oxygen at the bottom.
In this Dictionary, the semisystematic flavan-type nomenclature is given
precedence, substituents are ordered numerically and structures are drawn with

52
the oxygen heterocyclic atom at the bottom. In the Type of Compound Index,
most of the main classes of flavonoid are subdivided according to the number of
oxygen substituents.
4
6 5 3
A
7 8 2
O 1′ 2′ 3′
C
6′ 5′ 4′

Flavan
3,4-Dihydro-2-phenyl-2H-1-benzopyran
(S)-form shown

Further information about the nomenclature and numbering of each subclass

of flavonoid is given below.
A wealth of trivial names have been used for flavonoids. Some names
indicate the class of compound. For example, the ending ‘inidin’ denotes an
anthocyanidin (e.g. Pelargonidin) and the ending ‘etin’ a flavonol (e.g.
Quercetin). Likewise glycosides of Quercetin have related names such as
Quercitrin (the 3-rhamnoside), Isoquercitrin (the 3-glucoside) and
Quercimeritrin (the 7-glucoside). However, there is little consistency in such
use and many names have been derived from the generic or specific name of the
plant source (e.g. Tricin from Triticum, Corniculatusin from Lotus
corniculatus). A key to the trivial names most widely used for flavones and
flavonols may be found in Harborne (1988). There are a considerable number of
duplications of trivial names both between different flavonoids and between
flavonoids and other classes of natural product, e.g. terpenoids, alkaloids.

Anthocyanidins (VK0010–VK0070)
Anthocyanidins are intensely coloured plant pigments found throughout
vascular plants (they are replaced by purple betalain (alkaloidal) pigments in
one order of higher plants, the Centrospermae or Caryophyllales). The flavylium
chromophore in e.g. Cyanidin is cationic, being associated in vivo with organic
acid anions. The sugar-free anthocyanidin aglycones are relatively few and vary
according to the number and position of hydroxy and methoxy substituents.
Structural complexity is associated with the sugar substituents that are present in
the water-soluble anthocyanins. The anthocyanins range from simple structures
such as cyanidin 3-glucoside (Chrysanthemin) to Ternatin A1, a delphinidin
derivative which is substituted by seven glucose, four p-coumaric acid and one
malonic acid moiety. Some third of all the known anthocyanins have malonic
acid (or other aliphatic dicarboxylic acid) residues linked through sugar and are
zwitterionic in their properties.

6 5 4
3
7 8 2
O 1′ 2′ 3′
+ C
6′ 5′ 4′

Flavylium (2-phenylbenzopyrylium)

Flavans, Flavanols and Leucoanthocyanidins (VK1000, VK1100,

VK1200)
Flavans are formed by reduction of flavanones with flavan-3-ols as
intermediates. This is apparent from the facts that they may co-occur with the
related flavanone and that they have the same 2S configuration. There are a
small number of natural flavans, most of which are lipid soluble and occur
notably as leaf surface constituents. 4′,7-Dihydroxy-8-methylflavan, for
example, is a phytoalexin formed in the daffodil following fungal inoculation.

53
 The flavan-3-ols (or catechins) make up by far the largest class of monomeric
flavans. Two substances with the 3,3′,4′, 5,7-pentahydroxy substitution pattern,
namely Catechin and Epicatechin, are extremely widespread. Most flavan-3-
ols, such as Catechin, are of the 2R, 3S configuration. Those with the 2R, 3R
configuration are prefixed with ‘epi’, e.g. Epicatechin. Those with a 2S
configuration are distinguished by the enantio (ent-) prefix.

4 OH
6 5 3
A
7 8 2
O 1′ 2′ 3′
C
6′ 5′ 4′

Flavan-3-ol
3,4-Dihydro-2-phenyl-2H-1-benzopyran-3-ol
(2R,3R)-form shown

The term leucoanthocyanidin is used to designate all monomeric flavanoids

which produce coloured anthocyanidins by cleavage of a C-O bond on heating
with mineral acid. In addition to flavans and flavan-3-ols, there occur flavan-3,4-
diols and also a fourth but small class of flavans, the flavan-4-ols. Flavan-3,4-
diols are of biosynthetic importance, since they have recently been recognised
as the immediate precursors of the anthocyanins. Most naturally occurring 3,4-
diols have been obtained by extracting the heartwood of legume trees.
OH
4
OH
6 5 3
7 8 2
O 1′ 2′ 3′
C
6′ 5′ 4′

Flavan-3,4-diol
3,4-Dihydro-2-phenyl-2H-1-benzopyran-3,4-diol

Proanthocyanidins (VK1500)
Proanthocyanidin is the preferred name for condensed tannins (or flavolans), a
series of flavan-3-ol oligomers which are usually based on a C-C link from the
8-position of one flavan unit to the 4-position of a second unit. As with the
monomeric leucoanthocyanidins, they produce coloured anthocyanidins on
heating with mineral acid, but they have the additional property of binding to
protein. The best known proanthocyanidins are procyanidins, based on catechin
and/or epicatechin units, and oligomers up to the hexamer have now been found
in plants.
The interflavonoid linkage in proanthocyanidins is indicated in the same way
as for polysaccharides, the bond and its direction being contained in parentheses
(4→). The configuration of the interflavonoid bond at C-4 is indicated by the
IUPAC αβ nomenclature within the above parentheses. Thus two common
procyanidin dimers are described as Epicatechin-(4β→8)-catechin and ent-
Epicatechin-(4α→8)-epicatechin respectively. A considerable number of
doubly linked proanthocyanidins are known, where there is a second linkage
through C-2 to O-7. The naming of such compounds can be accommodated in
the same general way, e.g. one such compound is Epicatechin-(2β→7,4α→8)-
epicatechin. Many oligomeric proanthocyanidins with molecular sizes greater
than the hexamer, have been isolated from plants but their stereochemistries
have yet to be determined.

Biflavonoids and polyflavonoids (VK2000)

The structural variety present in biflavonoids is best illustrated with reference to
dimers of Apigenin (4′,5,7-trihydroxyflavone). Amentoflavone is the dimer in

54
which two apigenin units are linked by a carbon-carbon bond from the 8-
position of one unit to the 3′′′ of the other. A range of O-methyl ethers of this
basic structure occur naturally. Biapigenins with other C-C linkages have been
discovered, where the linkage is 3′-3′′′, 3-8′′, 3-3′′′, 6-8′′, 8-8′′, 6-6′′, or 6-5′′′.
Linkage through a C-O-C bond may also occur, as in Hinokiflavone, where the
two apigenin units are linked at the 6 and 4′′′ positions.
Mixed biflavonoids are also possible, e.g. flavone-flavanone dimers, as well
as compounds based on two flavanone units (e.g. Rhusflavanone). The first
triflavonoid has been reported recently, based on three units of Luteolin
(3′,4′,5,7-tetrahydroxyflavone). Biflavonoids have a distinctive distribution
pattern. There are major occurrences in gymnosperms, mosses and ferns and a
more limited presence in some 15 angiosperm families.

Isoflavonoids (VK3000–VK3100)
Isoflavonoids are based on the 3-phenylchroman skeleton that is biogenetically
derived by an aryl migration from a flavanone precursor. They have a very
limited distribution in the plant kingdom and are almost entirely restricted to the
subfamily Papilionoideae of the Leguminosae. They are found very occasionally
in about 18 other angiosperm families and there are isolated occurrences in
mosses and gymnosperms. Another striking feature about the isoflavonoids is
their major presence in lipophilic plant extracts in the free state and the relative
rarity of glycosidic derivatives.
Some isoflavonoid isolations reported from microorganisms are almost
certainly spurious, and associated with contamination from the culture medium.
The largest class of isoflavonoids are the isoflavones (VK3000–VK3070).
There are simple structures such as Genistein (4′,5,7-trihydroxyisoflavone) but
also a wealth of prenylated derivatives. The prenyl sidechains may ring-close on
adjacent hydroxyl groups, giving rise to tetracyclic and pentacyclic compounds.
The related isoflavanones (VK3100), in which the 2,3-bond is reduced, are
much rarer than the isoflavones.
O 2′ 3′ 4′
1′ 5′
4 6′
6 5 3
7 8 2
O
Isoflavone
3-Phenyl-4H-1-benzopyran-4-one

Rotenoid flavonoids (VK3200–VK3300)

Rotenoids are a class of isoflavonoid characterised by the presence of an extra
carbon atom in an additional heterocyclic ring. This system is derived by
oxidative cyclisation of a 2′-methoxyisoflavone. Rotenoids characteristically
possess insecticidal and piscicidal activity, as shown by Rotenone, one of the
parent structures. Besides rotenoids proper, there are a small number of 12a-
hydroxyrotenoid (VK3250) and dehydrorotenoid (VK3300) flavonoids, in which
there is a double bond introduced at the 6a–12a position.

55
 OMe
O 2 3 OMe
1
4
11 12
10 12a
98 6a 5
7 6 O
O O

Rotenone
1,2,12,12a-Tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)[1]
benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6aH)-one, 9CI

The numbering system most used by natural products scientists for Rotenone
is shown but other schemes have been used and it must be noted that the CA
scheme differs. Various numbering schemes have also been used for the cyclised
prenyl side-chain in Rotenone and similar compounds.

Pterocarpans (VK3400–VK3550)
Pterocarpans contain a tetracyclic ring system derived from the basic isoflavone
skeleton by an ether linkage between the 4- and 2′-positions. The systematic
numbering is distinctive for this particular carbon skeleton. The majority of
natural pterocarpans have been obtained from phytoalexin studies, so that in
general they possess antifungal activity. They are conveniently subdivided into
simple pterocarpan flavonoids, 6a-hydroxypterocarpan flavonoids and
pterocarpene flavonoids, in which unsaturation is introduced at the 6a–11a
position. The best known structure is Pisatin, a 6a-hydroxypterocarpan which is
the phytoalexin of the pea plant. Many isoprenylated pterocarpans have been
described and these substances constitute the second largest group of
isoflavonoids after the isoflavones. The commonly used numbering system
corresponds with the CA scheme.
10 9
O 8
11 7
11a
2 1 6a
34 5 6
O
Pterocarpan
6a,11a-Dihydro-6H-benzofuro[3,2-c][1]benzopyran, 9CI

Although pterocarpans have two chiral centres, only R,R and S,S
configurations are sterically possible. Most pterocarpan phytoalexins that have
been isolated are laevorotatory and have the 6aR, 11aR absolute configuration; a
few are dextrorotatory and can be assigned to the 6aS, 11aS series.

Isoflavans (VK3600–VK3700)
Isoflavans are another class of isoflavonoid which have been mainly isolated as
phytoalexins after fungal inoculation of plant tissues. They are also metabolites
of dietary isoflavones. Equol (4′,7-dihydroxyisoflavan) which has been isolated
from the urine of mammals, has estrogenic activity. The numbering system of
isoflavans is the same as that of the isoflavones.

3′ 4′
2′
1′
6′ 5′
5 4
6 3
7 2
8
O
Isoflavan
3,4-Dihydro-3-phenyl-2H-1-benzopyran

56
Coumestan flavonoids (VK3750)
One final group of isoflavonoids, numerically important in terms of numbers of
structures, are the coumestans. Like the isoflavans and many isoflavones, they
exhibit weak estrogenic activity in mammals. The simplest structure is
Coumestrol (7,9-dihydroxycoumestan) but a variety of prenylated derivatives
have also been characterised. The numbering system used is the same as in the
pterocarpan series and coincides with the CA systematic numbering.
O11 10
9
11a 8
7
2 1 6a
34 6
5
O O
Coumestan
6H-1-Benzofuro[3,2-c][1]benzopyran-6-one,9CI

Neoflavonoids (VK4000)
This term refers to a small group of C15 naturally occurring substances
structurally and biogenetically related to the flavonoids and isoflavonoids. They
have a limited distribution, occurring with isoflavonoids in the subfamily
Papilionoideae of the Leguminosae. Other families where they have been
encountered are the Guttiferae, Rubiaceae, Passifloraceae, Compositae and
Polypodiaceae.
There are three main subdivisions of structures: the 4-arylcoumarins, the
dalbergiones and the dalbergiquinols. Representative structures, all isolated from
Dalbergia species, are the ring-closed Dalbergin and the two related ring-
opened compounds, 4-Methoxydalbergione and Obtusaquinol. Prenylated
derivatives of the 4-arylcoumarins have been characterised in the Guttiferae.

Flavones and Flavonols (VK5000–VK5280)

Flavones are a class of polyhydroxyflavonoid based on the structure of Flavone
(2-phenyl-4H-1-benzopyran-4-one or phenylchromone) which itself occurs
naturally as a farina on Primula plants. Flavonols are flavones with a 3-hydroxy
substituent and they share the same nomenclature. It is convenient to separate
these two classes, mainly because so many structures are known; some 1000
aglycones and over 2,000 glycosides. They differ in their spectroscopic and
chromatographic properties and can readily be distinguished by these means.
They are biosynthetically distinct, flavones being formed by oxidation of
flavanones, flavonols by oxidation of dihydroflavonols. There are also
differences in the way they occur naturally; C-glycosides are common in the
flavone series but rare among flavonols.
In the DNP Type of Compound Index they are subdivided according to the
number of O substituents (including methylenedioxy groups): C-methylation
and C-prenylation is relatively common.
Free lipophilic flavones and flavonols occur at the upper surface of leaves in
the wax or in bud exudates. There are also many O-glycosides, which are found
within the leaf in the cell vacuole and in other parts of the plant. There are at
least 200 different glycosides of Quercetin and 250 of the related flavonol,
Kaempferol. (The principal derivatives of such widespread parent flavonoids
have their own entries in DNP and it is important to use the indexes to locate a
particular glycoside which may be documented in one of these subsidiary
entries).

57
 O O

6 5
4
3 6 5
4
3
OH
A
7 8 2 7 8 2
O 1′ 2′ 3′ O 1′ 2′ 3′
C C
6′ 5′ 4′ 6′ 5′ 4′

Flavone Flavonol
2-Phenyl-4H-1-benzopyran-4-one 3-Hydroxy-2-phenyl-4H-1-benzopyran-4-one

In DNP individual flavonols are named both as derivatives of an n-

hydroxyflavonol and as derivatives of an (n + 1) hydroxyflavone, allowing their
rapid location through the indexes whichever name is employed. The flavonoid
alkaloids e.g. Ficine, are described under the alkaloids (VX 0350)

Chalcones and dihydrochalcones (VK6010–VK6080, VK6200)

Chalcones are open-chain C6-C3-C6 compounds, the first intermediates of
flavonoid biosynthesis. They occur sporadically in plants as yellow pigments,
some 200 structures being known. The numbering system of chalcone
substituents differs from that in ringclosed flavonoids.
O

3′ 2′ 1′
α
A
4′ 6′
5′ β 1 2 3
C
6 5 4

Chalcone
1,3-Diphenyl-2-propen-1-one, 9CI

Note that the numbering of the A ring is the same in both systems of
nomenclature, but the C ring is unprimed in the semitrivial chalcone system and
carries a double prime if systematic numbering is used (the α- and β-positions
becoming 2 and 3 respectively). The majority of chalcones have
hydroxy/methoxy substituents at the 2′,4,4′,6′-positions, and a significant
number of prenylated derivatives are known.
In dihydrochalcones, the double bond in the α-β-position is reduced and the
compounds are colourless. The numbering system is the same as in the chalcone
series. They are less common than chalcones and occur variously in higher
plants, ferns and liverworts.

Aurone flavonoids (VK6100)

Aurones are a small group of yellow pigments, based on the 2-
benzylidenecoumaranone nucleus. These are formed by oxidation of chalcones
and may co-occur with the related chalcone precursors. The numbering system
differs from that in the chalcone series, so that the most common hydroxylation
pattern, that of the pigment Aureusidin, is 3′,4,4′,6-tetrahydroxyaurone. Note
the potential occurrence of geometrical isomers.
O
4 3
5
A 2
6 7
O 1′ 2′ 3′
C
6′ 5′ 4′

Aurone
2-(Phenylmethylene)-3(2H)-benzofuranone, 9CI

The auronols (2-hydroxy-2-benzylcoumaranones) are a closely related series

of colourless compounds, with only a few members so far described.

58
Flavanones (VK6300–VK6380)
Flavanones are 2,3-dihydro-2-phenyl-4H-1-benzopyran-4-ones. The simplest
known natural flavanone is the 7-hydroxy derivative, while the commonest is
4′,5,7-trihydroxyflavanone (Naringenin). Flavanones are isomeric with
chalcones and arise biosynthetically from them by a reaction catalysed by an
isomerase. They have a centre of chirality at C-2 and usually occur in optically
active form with the 2S-configuration. They commonly occur as glycosides. A
variety of more complex derivatives with methyl and/or prenyl substituents has
been described. Flavanones have a wide occurrence in plants.
O
4
6 5 3
A
7 8 2
O 1′ 2′ 3′
C
6′ 5′ 4′

Flavanone
2,3-Dihydro-2-phenyl-4H-1-benzopyran-4-one, 9CI
(S)-form shown

Dihydroflavonols (VK6410–VK6470)
Dihydroflavonols can be described as 3-hydroxyflavanones or as flavanon-3-ols.
They are formed biosynthetically by oxidation at C-3 of flavanones, without
inversion at C-2, and are the immediate precursors by a further oxidation of the
flavonols. Dihydroflavonols have two chiral centres at C-2 and C-3; most
naturally occurring compounds possess the (2R,3R) stereochemistry.
Dihydroflavonols such as Dihydroquercetin have a wide occurrence in nature
being present in the free state in woody plant tissues. They also occur in
glycosidic combination in other plant parts.

O
4
OH
6 5 3
A
7 8 2
O 1′ 2′ 3′
C
6′ 5′ 4′

Dihydroflavonol
2,3-Dihydro-3-hydroxy-2-phenyl-4H-1-benzopyran-4-one, 9CI
(2R,3R)-form shown

59
Tannins (VM)
Plant polyphenols (vegetable tannins) are secondary metabolites widely
distributed in the plant kingdom. They are based upon two broad structural
themes:
(a) Condensed proanthocyanidins in which the fundamental structural unit is
the phenolic flavan-3-ol (catechin) nucleus.
(b) Galloyl and hexahydroxydiphenoyl esters and their derivatives.
These metabolites are almost invariably found as multiple esters of 3,4,5-
trihydroxybenzoic (gallic) acid with D-glucose and a great many can be envisaged
as derived from the key biosynthetic intermediate β-1,2,3,4,6-pentagalloyl-D-
glucose. Derivatives of hexahydroxydiphenic acid are assumed to be formed by
oxidative coupling of vicinal galloyl ester groups in a galloyl-D-glucose ester.

OH OH
HO OH O HO OH O
O O
–2H

O O O O
HO OH HO OH
OH OH

galloyl ester hexahydroxydiphenoyl ester

(G) G-G

Gallic acid is most frequently encountered in plants in the form of esters.

These may be classified into several broad categories:
(a) Simple gallate ester tannins. (VM6000).
(b) Depside metabolites (gallotannins).
(c) Hexahydroxydiphenoyl and Dehydrohexahydroxydiphenoyl ester tannins
(ellagitannins) based upon:
(i) 4C1 conformation of D-Glucose.
(ii) 1C4 conformation of D-Glucose.
(iii) ‘open-chain’ derivatives of D-Glucose.
(d) Dimers and higher oligomers formed by oxidative coupling of monomers,
principally those of class (iii) above.
Four distinctive and principal pathways are presumed to lead from β-1,2,3,4,6-
pentagalloyl-D-glucose and to give, by appropriate chemical embellishment the
various classes of metabolites (Figure 10).
Ellagitannin metabolites fall into two broad categories – monomeric species
formed by intramolecular C-C oxidative coupling and oligomeric species
formed by intermolecular C-O coupling (Figure 11). Numerous intramolecular
C-C linked ester groups have been located in the monomers and similarly
various intermolecular C-O linking ester groups have been defined in the
formation of the oligomeric structures. The principal members of these two
classes of ester group are shown in Figures 12–15.
The nomenclature and numbering of the more complex types of tannin is
difficult. CA names them as complex carbohydrate esters or (in the more
complicated cases, e.g. Vescalagin as stereoparents, with closely related natural
products being named as derivatives, e.g. Castavaloninic acid = 25-O-(6-
carboxy-2,3,4-trihydroxyphenyl)vescalagin, 9CI. In such cases the numbering is
arbitrary. In DNP, limited numbering of structures is shown only when it is
strictly necessary.
The various subclasses of tannin are separately listed in the Type of
Compound Index according to the esterifying acid group, beginning with simple
gallate esters and proceeding to the more complex types.

60
 Pathway (B) Oxidative coupling, Pathway (D) Oxidative
Dehydrogenation, 4-6 and 3-3; coupling, ring opening
Oligomerisation by C-O coupling -open chain derivatives
ellagitannins ellagitannins

–[H]n
–[H]n
OG
6
4
GO O
G = Galloyl ester 2 OG
GO 1
3
OG
β-1,2,3,4,6-Pentagalloyl-D-glucose
D-glucopyranose4C1 conformation

COOH

GO 6
OG OG HO OH
1
O OH
4 3 2

OG OG
β-1,2,3,4,6-Pentagalloyl-D-glucose
D-glucopyranose1C4 conformation

Pathway (A) Additional galloyl

groups esterified as m-depsides to
–[H]n
the preformed galloylglucose
gallotannins

Pathway (C) Oxidative coupling,

Dehydrogenation, 3-6, 1-6 and 2-4;
Dehydrohexahydroxydiphenoyl esters
ellagitannins

Figure 10. Biogenesis of the gallotannins and ellagitannins; the metabolic

embellishment of β-1,2,3,4,6-pentagalloyl-D-glucose, principal pathways.

Haslam, E. (1982) Prog. Chem. Org. Nat. Prod., 41, 1.

Haslam, E. (1982) Plant Polyphenols – Vegetable Tannins Revisited, Cambridge
University Press, Cambridge.
Haslam, E. (1994) Nat. Prod. Rep., 11, 41.
Okuda, T. et al. (1981) Heterocycles, 15, 653.
Okuda, T. et al. (1989) J. Nat. Prod., 52, 1.
Okuda, T. et al. (1989) Planta Med., 55, 117.
Okuda, T. et al. (1990) Heterocycles, 30, 1195.
Okuda, T. et al. (1993) Phytochemistry, 32, 507.
OKuda, T. et al. (1995) Prog. Chem. Org. Nat. Prod., 66, 1.
Schmidt, O. Th. (1956) Prog. Chem. Org. Nat. Prod., 13, 570.

β-1,2,3,4,6-pentagalloyl-D-glucose

–[H] intramolecular
C-C coupling

hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl

esters ('monomers')

intramolecular
–[H]
C-O coupling

[hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl

esters]n (oligomers, n = 2,3,4)
n

Figure 11. Overall patterns of oxidative metabolism of β-1,2,3,4,6-pentagalloyl-D-

glucose in higher plants to yield ellagitannins.

61
 OH OH
HO OH HO OH OH
HO
OH OH
HO HO HO
OC OC CO
HO HO O
CO CO
O OH
(R)-Hexahydroxydiphenoyl (S)-Hexahydroxydiphenoyl OH
VM 6100 VM 6100 HO
OH HO O
HO OH
O
OH OH CO
HO
HO OH
OC HO
HO CO OC OH OH
Gallagyl
VM 7600
Flavogallonoyl
VM 7000, VM 7050

Figure 12. Principal derivatives of hexahydroxydiphenic acid formed by intramolecular

C-C oxidative coupling.

O
O
O O

L-Ascorbic acid OH O O
O OH
O O O HO HO OH OH
CO
O OC OH
HO OH CO
OH
OH O O
O O O O
O O
O HO OH O
O O
Dehydrohexahydroxy-
Elaeocarpusinoyl diphenoyl HO
VM 6300 VM 6200
O OH
OH
O
HO
OH

Figure 13. The dehydrohexahydroxydiphenoyl ester group and its derivatives.

O O

O OC O OC
CO OH CO OH
HOOC OH HOOC OH
H
O O
HO HO
O O
Chebuloyl Dehydrochebuloyl
(VM 6500) (VM 6400)
OH
OH

O OH
CO
OC
O CO OH
OC
CO OH
OH
OH HOOC OH
H
O O
O HO
Brevifoloyl O
(VM 6600) Trilloyl

Figure 14. Ester derivatives of hexahydroxydiphenic acid in which one aromatic ring
has undergone hydrolytic cleavage.
62
 OC HO OH HO OH
OH O CO HO OH
HO
HO OH O CO OC
OH
CO HO OH
(S)-Sanguisorboyl
Dehydrodigalloyl VM 6900
VM 6700

OC
HO OH HO OH
HO O O OH
OH HO OH HO
HO OH
CO OC OC OH HO OH
OH CO OC
Valoneoyl
VM 6800, VM 6820, VM 6850 (R)-Tergalloyl
VM 7300, VM 7350

OH OH
OC OH OC OH
OH OH
O O
HO OH OH OH HO OH
HO OH CO O OH

CO OC OH CO OC

(R)-Macaranoyl HO OH
VM 7200 (R)-Euphorbinoyl
VM 7500
Figure 15. Principal ester groups formed by intermolecular C-O oxidative coupling of
galloyl and hexahydroxydiphenoyl esters.

63
Lignans (VO)
The lignans are a group of plant phenols whose structures are determined by the
union of cinnamic monomers or their biogenetic equivalents. The lignan dimers
linked at β-positions in the side chain were first defined in 1936 by R.D.
Haworth and these are discussed first. This group of about 900 compounds has
since been extended to include some 500 neolignans, which are dimerised in
other ways, and higher oligomers of cinnamyl alcohols. Higher lignoid
polymers occur in wood as lignin and are degraded during papermaking
processes.
9′
7
8 8′
7 9 – MeO 7′
COO
3 2 1 9
8 HO
45 6

OMe
Cinnamate monomer
OH
Dihydroguaiaretic acid

O O

O 7′ 7 O
8′ 8
9′ 9
O
O
Hinokinin

The rings may bear different oxysubstituents and trioxygenation is common.

Dihydroguaiaretic acid illustrates one typical aromatic substitution pattern and
Hinokinin another. A single para-phenolic substituent is rare but this position is
always occupied since the biosynthesis depends upon it. Free carboxylate
groups are rare; ketals and ketones are found occasionally. The presence of an
oxysubstituent para to the side chain in lignin and all lignans is consistent with
a biosynthesis via coupling of mesomeric cinnamoyl radicals derived from a
coumaryl alcohol.
The same net result would be obtained by two stage process initiated through
the attack of such a radical upon its phenolic precursor. Growth of polymeric
lignin can be rationalised through radical sites located on oxygen, on the ring
system or in the side chain, whilst dimerisation of the latter leads to structures
such as Dihydroguaiaretic acid and Hinokinin.
Lignans have been obtained as fragments from the degradation of lignin and
direct evidence of lignan biosynthesis which substantiated the lignin analogy
was obtained in 1969, when it was shown that cinnamyl precursors were
incorporated into Podophyllotoxin. This work was subsequently extended by
other workers who established this route in butyrolactones and furofurans.

CH2OH CH2OH
(RO) +
(RO)
–H
HO –e O
–

CH2OH CH2OH
(RO) – (RO)

O O –

The oxidation level of the cinnamyl residues when coupling occurs is

uncertain and related studies are complicated by interaction of the matrix of
lignan precursors with the larger lignin pool. It is commonly believed that lignin
formation is not under enzymic control because lignin, in contrast to lignans, is

64
 not optically active. However, it is possible that in lignin internal compensation
occurs between the many chiral centres.
Dihydroguaiaretic acid and Hinokinin are representatives of major classes
which are sometimes loosely referred to as ‘acyclic’; others may be defined as
either carbocyclic or oxy-heterocyclic derivatives of these two types of parent.
The lignans are classified in the Type of Compound Index essentially
according to Figure 16 which illustrates the principal lignan types including the
unusual 7′,8-structure found in Magnosalicin.
The systematic nomenclature of such a structurally diverse, though
biogenetically related, group of compounds is of limited utility and easily
disguises structural similarities. The CA names of most lignans are given as
synonyms within the entries, but the entry name is usually either a trivial name
or a semisystematic name using the system originally proposed by Freudenberg
and Weinges which has been extended by Moss and now accepted by IUPAC.
This names lignans according to a ‘lign-’ scheme which more accurately reflects
their biosynthetic origin. The cinnamyl unit of higher priority is numbered from
1–9 while that of lower priority bears primed numbers.
For Dihydroguaiaretic acid the two cinnamyl residues are equivalent so that
no distinction need be made between them and the semi-systematic name is:
4,4′-dihydroxy-3,3′-dimethoxylignan. Note that under the CA system this
compound would be named as a phenol. In Hinokinin, the sequence rules
require that priority be given to the lactone carbonyl (C9) and this leads to the
lignan name 3,3′,4,4′-bis (methylenedioxy)lignan-9,9′-olide.
Natural lignans are optically active although a few meso-compounds are
known. Important physiological properties may be associated with a particular
absolute configuration, as for example with the antitumour agent

Simple dibenzylbutane lignans Dibenzylbutyrolactone lignans

(V0050, VO0100) (VO0150, VO0200)
7′ 9′
8′

8 O
9
7
O

9.9′-Lignanolide
9
Furanoid lignans
9′ 8
9 9′ 8′ 7 9 7′
7′
8 8′ O 8′ 7′
8 8′
7 7′ 7 9′
O O
O

7,8′-Epoxylignans 7,9′-Epoxylignan
7,7′-Epoxylignan (VO0300)
(VO0280)
(VO0350)

Furanoid lignans Simple aryltetralin lignans Dibenzocycloctadiene lignans

9
O 7 8

9′ 7 2 8′ 7′
7′ 2′ 9′
9′
8′ 8 8′
7′ 9
2 8
O 7
9

7,9′:7,9′-Diepoxylignan 2,7′-Cyclolignan 2,2′-Cyclolignan

(VO0400, VO0450, VO0470) (VO0500, VO0550, VO0600, (VO0750)
VO0650, VO0700)

Figure 16. Lignan structural types.

65
 Podophyllotoxin. The application of the Cahn-Ingold-Prelog sequence rules to
lignans needs to be done with care as apparent inversions of configuration
between closely related compounds owing to different substitution patterns are
common.
Inherent dissymmetry is shown by some semisynthetic derivatives of
Podophyllotoxin and in the dibenzocyclooctadienes. The absolute configuration
of the latter major group is securely based on the X-ray analysis of Gomisin D.
This is an atropoisomer with the S-configuration.

Neolignans (VO1500)
These compounds are also dimers of cinnamyl units but their structures are
obtained by coupling of mesomeric radicals other than the β-β link typical of
the lignans.
As the range of lignoids and their plant sources has widened so the distinction
between lignans and neolignans has become less significant. Thus the neo-
lignans were long – identified as more typical of plants of the family Lauraceae,
but in recent years they have been isolated from the Piperacae, Magnoliaceae,
Phytolaccacae, Rutaceae, Pinaceae and Berberidaceae amongst others. Further,
lignans and neolignans frequently occur in plants of the same family, for
example in Piper wightii. Significant developments were the isolation of the
classical lignan Megaceratonic acid from a non-vascular plant – the hornwort
Megaceros flagellaris, and of the pyranonyl hybrid Scapaniapyrone and its
analogue from the liverworts Scapania undulata and Jamesoniella autumnalis
respectively: at present only 5% of liverworts have been investigated.
The system of nomenclature illustrated above extends logically to include
both neolignans and oligomeric lignoids since all are produced by the union of
mesomeric cinnamate radicals. The structures (Figure 16) show the
permutations of radical couplings at 8,8′-positions in lignans and some of the
more varied combinations based on C-C and C-O linkages in neolignans are
shown in Figure 17.

Sesquilignans and dilignans

In recent years a significant number of these oligomers has been identified
largely owing to the use of HPLC allied to mass spectroscopy. Typical of the

9 9′

3 3′ 8′
3 1
Ar Ar 8′

Ar Ar

8′
O
1
8 3
4′
O Ar
8′ 4
8′
Ar Ar
Ar

3′ O
O
4 8′
3
8′ 7′ 1
1
O Ar O
Ar

Figure 17. Skeletons of some neolignans.

66
former group are the lappaols including Lappaol A, with three linked cinnamate
residues. Manassantin B including four such residues is typical of the
dilignans.
Note the variation in bond type between the classical C – C bonding in
Dunnianol and that in Salvianolic acid, which is regarded as a member of this
group although on hydrolysis of the enol ether and ester linkages the lignoid
character will be lost altogether. A similar distinction needs to be drawn
between the dilignans Arctigenin E and Buddlenol E, where four residues may
be stably linked through C – C bonds or through a combination of C – C and
ether linkages, and Cannabisin G. The latter falls within the definition of a
dilignan yet on hydrolysis yields the arylethylamine and a ligna-dienoic acid.

Hybrid lignans
Here the lignoid includes a structure typical of another class of natural product:
with the increased sensitivity of modern isolation methods the list of both
members and known structural types is expanding. Silybin is a flavonolignan
and in 1968 was the first known hybrid to be described; the coumarinolignan
Cleomiscosin followed in 1979. Pseudotsuganol is illustrative of another type
of flavonolignan.
More recently the stilbenolignan Maackolin and the xantholignan Cadensin
G have been identified. Hybrid terpenes are typified by the C – C linked
Piperitylmagnolol and by the C – O linked Eudesmagnolol. In Chilianthin A
the lignan acid is esterified with an oleanyl triterpene. The hydrolysable
macrocycle Pelliatin is of interest structurally and also because it is a
constituent of a non-vascular plant, the liverwort Pellia epiphylla.
O
OH
HO

OH
HO O
HO

OH
O
OMe

H H

O
HO
OMe
Pseudotsuganol

Ayres, D.C. and Loike, J.D. (1990) Lignans, Chemical, Biological and Clinical
Properties, Cambridge Univ. Press, Cambridge.
Fengel, D. and Wegener, G. (1984) Wood: Chemistry, Ultrastructure and Reactions, de
Gyten, Berlin.
Freudenberg, K. and Weinges, K. (1961) Tetrahedron, 15, 115 (nomenclature).
Gottlieb, O.R. (1978) Prog. Chem. Org. Nat. Prod., 35, 1 (neolignans).
Gottlieb, O.R. and Yoshida, M. (1989) in Natural Products Extraneous to the
Lignocellulosic Cell Wall of Woody Plants (eds J.W. Rowe and C.H. Kirk)
Springer, Berlin (neolignans).
Haworth, R.D. (1936) Ann. Rep. Progr. Chem., 33, 266.
Lin, L-J. and Cordell, G.A. (1984) Chem. Commun., 160 (coumarinolignans).
MacRae, W.D. and Towers, G.H.N. (1984) Phytochemistry, 23, 1207 (activity).
Marston, A. and Hostettman, K. (1991) Nat. Prod. Rep., 8, 392 (sesquilignans,
dilignans).
Sakakibara, A. et al. (1987) Holzforschung, 41, 1.
Ward, R.S. (1993) Nat. Prod. Rep., 10, 1; 1995, 12, 183; 1997, 14, 43 (rev).

67
Polycyclic aromatic natural
products (VQ)
A large proportion of the polycyclic aromatic compounds encountered in nature
are quinonoid.
Quinone and quinonoid compounds are widely distributed and exist in all
living organisms, often playing an important role in redox systems.
The quinones isolated from higher plants are usually relatively simple and
frequently present as glycosides. The microbial quinones, on the other hand, are
often more complex and exhibit greater structural diversity as well as wider
variations in biological activity.

Eckardt, K. (1981) in Antitumour compounds of natural origin, Chemistry and

Biochemistry (ed. A. Aszalos) CRC Press, Boca Raton, II, 28.
Gill, M. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 60.
Simpson, T.J. (1984) in The Chemistry of Natural Products (ed. R.H. Thomson),
Blackie, Glasgow, pp. 107.
Thomson, R.H. (1971) Naturally Occurring Quinones, 2nd edn. Academic Press,
London.
Thomson, R.H. (1987) Naturally Occurring Quinones III, Chapman & Hall, London.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Naphthalenes and naphthoquinones (VQ2000, VQ3000–VQ3060)

Most of the naphthalene derivatives found in nature are naphthoquinones, which
are listed in the Type of Compound Index subdivided according to their number
of oxygen substituents. They may arise by polyketide, terpenoid, shikimate
pathways or a mixture of these. The purely terpenoid naphthalene derivatives
are listed in the Terpenoid section under their biogenetic class.

Benzoisochromanquinones (VQ3100)
These are of polyketide origin and are found in fungi.
O O
8 1
7 2
6 3
O
5 4
O O

Naphthoquinone Benzoisochromanquinone
1,4-Napthalenedione, 9CI

Binaphthyls, perylenes and the duclauxin group (VQ2500, VQ2600,

VQ2700)
Binaphthyls and perylenes arise by radical coupling of naphthylenes. The
Duclauxin group arises from radical coupling of a naphthopyran derivative.
3 4
2 5
1 6

12 7
11 9 8
10

Binaphthyl Perylene, 9CI

[1,1′-Binaphthalene], 9CI

68
Turner, W.B. (1971) Fungal Metabolites, Academic Press, London.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.
Weiss, U. et al. (1987) Prog. Chem. Org. Nat. Prod., 52, 1.

Indenes and Indan-1-spirocyclohexanes (VQ3300, VQ3400)

Simple natural indenes are listed under this heading apart from those of
terpenoid origin that are listed in the appropriate Terpenoid section. The indan-
1-spirocyclohexanes are found in cannabis and are probably derived
biosynthetically from dibenzyls.

7 1
6 2
5 3
4

Indene Indan-1-spirocyclohexane

Crombie, L. et al. (1982) J. Chem. Soc., Perkin Trans 1, 1455.

Anthracenes and phenanthrenes (VQ3450, VQ4000–VQ4200,

VQ4800–VQ5100)
Anthraquinones are the largest class of natural quinones. They are generally of
polyketide origin. 9,10-Anthaquinones, which are listed subdivided according to
their number of oxygen substituents, predominate with a small number of 1,2-
and 1,4-anthraquinones (VQ4100). Bianthracenes presumably arise by radical
coupling mechanisms. A number of non-quinonoid oxygenated phenanthrenes
and 9,10-dihydrophenanthrenes are found in higher plants. 1,2-, 1,4- and 9,10-
phenanthraquinones are also found as natural products in higher plants and
fungi.
O
3 2
10 4
8 1 1
7 2
6 3
5 9 4 5
6
7 10
O 8 9

9,10-Anthraquinone Phenanthrene
9,10-Anthracenedione, 9CI

Bolton, R. (1988) in Rodd’s Chemistry of Carbon Compounds, Suppl., (ed. M.F.

Ansell), Elsevier, Amsterdam, Vol. IIIH, 1.
Gill, M. et al. (1987) Prog. Chem. Org. Nat. Prod., 51, 1.
Sainsbury, M. (1979) in Rodd’s Chemistry of Carbon Compounds, 2nd edn, (ed. S.
Coffey), Elsevier, Amsterdam, Vol. IIIH, 1.
Sargent, M.V. (1984) Prog. Chem. Org. Nat. Prod., 45, 103.
Thomson, R.H. (1971) Naturally Occurring Quinones, 2nd edn, Academic Press,
London.
Thomson, R.H. (1987) Naturally Occurring Quinones III, Chapman & Hall, London.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.
Wijnsma, R. et al. (1986) Prog. Chem. Org. Nat. Prod., 49, 79.

Anthracyclinones (VQ4300)
The anthracyclines produced by Streptomyces form a group of clinically useful
antitumour agents. They also show potent activity against gram-positive bacteria
but are generally too toxic to be of value. In addition to the 200 or so naturally
occurring metabolites, many semisynthetic anthracyclines have been developed
in the search for improved antitumour activity and lower toxicity. Biosynthesis

69
is from a decaketide precursor formed from nine acetates and one propanoate
unit.
Numbering of anthracycline derivatives is confusing. The IUPAC numbering
system is commonly used. However CA names them systematically as
substituted naphthacenediones and in these cases the numbering depends on the
hierarchy of the attached functional groups.
O COOR O
1 12 10
COR 4
9 8

4 5 6 7 1 12 10
O O O O

IUPAC CA, e.g. Daunomycin

O COOR
11 1
2
8
6 4
O O

CA, e.g. Pyrromycin

Behal, V. et al. (1983) in Biochemistry and genetic regulation of commercially

important antibiotics (ed. L.C. Vining) Addison-Wesley, pp. 255.
Eckardt, K. et al. (1988) J. Basic Microbiol, 28, 137 (biosynth).
Fujiwara, A. et al. (1986) CRC Crit. Rev. Biotechnol. CRC Press, Boca Raton, 3, 133
(struct, biosynth).
Kelly, T.R. (1984) Tetrahedron, 40, 4537 (synth)
Krohn, K. (1986) Angew. Chem. Int. Ed., 25, 700 (synth).
Lown, J.W. (ed.) (1988) Bioactive Reviews Vol. 6, Elsevier, Amsterdam.
Thomas, G.J. (1990) Recent Prog. Chem. Synth. Antibiot., 467 (synth)
Vigevani, A. et al. (1985) Mag. Reson. Chem., 23, 344 (pmr, ir).
Wagner, C. et al. (1991) J. Basic Microbiol., 31, 223 (biosynth).

Extended quinones (VQ6000)

Extended quinones arise from simpler precursors by oxidative phenol coupling.
Natural diphenanthroquinones have not been found. There are only a few
extended o-quinones. The dinaphthoquinones and dianthroquinones may be
further coupled to give perylene and similar ring systems.
O O

O O

Dibenzoquinone Dinaphthoquinone

Thomson, R.H. (1971) Naturally Occurring Quinones, 2nd edn. Academic Press,
London.
Thomson, R.H. (1987) Naturally Occurring Quinones III, Chapman & Hall, London.

Phenalenes and fluorenes (VQ7500, VQ7700)

There are only a small number of natural products with the phenalene and fully
aromatic fluorene skeletons.

70
 1 2 3 1 2

3 5 4
9 4 8 6 3
8 5 7 4 7 2
7 6 6 5 8 9 1

Phenalene Acenaphthene Fluorene

Andrew, H.F. (1979) in Rodd’s Chemistry of Carbon Compounds, 2nd edn. (ed. S.
Coffey), Elsevier, Amsterdam, Vol. IIIH, 138.
Andrew, H.F. (1988) in Rodd’s Chemistry of Carbon Compounds, Suppl., (ed. M.F.
Ansell), Elsevier, Amsterdam, Vol IIIH, 27.
Cooke, R.G. et al. (1981) Prog. Chem. Org. Nat. Prod., 40, 153.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Miscellaneous polycyclic aromatics (VQ9000)

Miscellaneous polycyclic aromatic systems that occur naturally probably arise
by radical coupling of simpler systems.

Andrew, H.F. (1988) in Rodd’s Chemistry of Carbon Compounds, Suppl., (ed. M.F.
Ansell), Elsevier, Amsterdam, Vol. IIIH, 71.
Campbell, N. et al. (1979) in Rodd’s Chemistry of Carbon Compounds, 2nd edn. (ed. S.
Coffey), Elsevier, Amsterdam, Vol. IIIH, 211.

71
Terpenoids (VS)

Classification of terpenoids
The immense variety of structural types found in the terpenoids was rationalised
by the isoprene rule of Ruzicka. However, the number of exceptions to the
regular arrangement of isoprene units led to the biogenetic isoprene rule which
encompassed the possibility of rearrangements during biosynthesis. Terpenoids
are thus seen as being formed from linear arrangements of isoprene units
followed by various cyclisations and rearrangements of the carbon skeleton.
They can also be biosynthetically modified by the loss or addition of carbon
atoms. It is useful to classify terpenoids according to the number of isoprene
units from which they are biogenetically derived, even though some carbons
may have been added or lost. (This sometimes causes some uncertainty if it is
believed that more than five carbons have been lost; only a biosynthetic study
can resolve this issue. For example the irones (C15) are derived biosynthetically
from the iridial group (C31)).
The biogenetic isoprene rule implies the involvement of a branched five
carbon unit in the biosynthesis of terpenoids. Isoprene, although a natural
product, is not a precursor of the terpenoids. The biosynthetic origin of this five
carbon unit is well established. The pathway involves mevalonic acid which is
converted into isopentenyl diphosphate, the five-carbon precursor of the
terpenoids. However alternative biosynthetic pathways to isopentenyl
diphosphate are now becoming common.
HO

HOH2C COOH
Isoprene Mevalonic acid

O O
CH2O C O P OH
OH OH
Isopentenyl diphosphate

There are a few naturally-occurring branched C5 compounds. These are listed

in the Type of Compound Index under Hemiterpenoids (VS0050).
Chappell, J. (1995), Ann. Rev. Plant Physiol. Plant Mol. Biol., 46, 521.
Dewick, P.M. (1997), Nat. Prod. Rep., 14, 111
Hanson, J.R. (1997) in Comprehensive Organic Chemistry (eds D.H.R. Barton et al.),
Pergamon, Oxford, Vol. 5, p. 989.
Loomis, W.D. et al. (1973) Recent Adv. Phytochem., 6, 147.
Ramos-Valdivia, A.C. et al. (1997) Nat. Prod. Rep., 14, 591.
Ruzicka, L. et al. (1921) Helv. Chim. Acta, 4, 505.
Ruzicka, L. et al. (1953) Experientia, 9, 357.
Ruzicka, L. (1959) Proc. Chem. Soc., 341.

Nomenclature
The systems used for the nomenclature of terpenoids have evolved over a long
period. For many terpenoid classes more than one name has been proposed for
the carbon skeleton and in a large number of cases several numbering systems
are in use. DNP has used the most accepted numbering system for most skeletal
types. In cases for which no numbering system has been proposed or where
several are in use, preference has been given to the biogenetic system.

72
 Many terpenoids are named as formal variants of steroid structures and their
nomenclature and numbering therefore follows on from that of steroids, which
is described more fully in a subsequent section.

Monoterpenoids (VS0100–VS1200)
Monoterpenoids have been isolated from the fragrant oils of many plants and
are important in the perfumery and flavour industries. Monoterpenoids are also
found in many marine organisms, where they are generally halogenated, and as
insect pheromones and defence secretions. The biosynthetic pathways of the
main classes of monoterpenes have been well studied.

Banthorpe, D.V. et al. (1972) Chem. Rev., 72, 115.

Croteau, R. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J.W. Porter et al.),
Wiley, New York, Vol. 1, p. 225.
Croteau, R. (1987) Chem. Rev., 87, 929.
Croteau, R. et al. (1994), Recent Adv. Phytochem., 28, 193.
Grayson, D.H. et al. (1997) Nat. Prod. Rep., 14, 477.
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (Ed. R.H. Thomson),
Blackie, Glasgow, pp. 107.
Lerdau, M. (1994), Trends Ecol. Evol., 9, 58.

Acyclic monoterpenoids (VS0100)

In this section are grouped the regular linear monoterpenoids, that is those
formed by a head to tail arrangement of the isoprene units. They are principally
found in plants and in insect exudates. No semi-systematic name has been
ascribed to this carbon skeleton probably because the systematic 2,6-
dimethyloctane naming is straightforward. The numbering system shown below
is in line with that used with other acyclic terpenoids.
9 10

7 5 3 1
8 6 4 2

Regular acyclic monoterpenoid skeleton

2,6-Dimethyloctane, 9CI, 8CI

Irregular acyclic monoterpenoids (VS0150)

Some acyclic monoterpenoids arise from other arrangements of the isoprene
units. These may arise by alternative linkages of the units, e.g. head to head, by
rearrangement of regular acyclic monoterpenoids or by cleavage of cyclic
monoterpenoids.

Irregular acyclic monoterpenoid skeletons

Halogenated dimethyloctane monoterpenoids (VS0200)

This group is obtained principally from marine organisms. They are all regular
acyclic monoterpenoids and the numbering system follows the accepted pattern.

Naylor, S. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 189.

73
Ochtodane monoterpenoids (VS0220)
The ochtodanes are also principally from marine organisms particularly
Ochtodes spp. and presumably arise by cyclisation of myrcene.
2
4
5 3 1
6 8
7

9 10

Myrcene Ochtodane
3-Ethyl-1,1-dimethylcyclohexane, 9CI

Naylor, S. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 189.

1-Ethyl-1,3-dimethylcyclohexane and 1-ethyl-2,4-dimethylcyclohexane

monoterpenoids (VS0240, VS0260)
These two terpenoid skeletons are only found in marine organisms and
presumably arise by cyclisation of a regular acyclic monoterpene skeleton
followed in the latter case by an ethyl migration. The numbering systems reflect
their probable biogenetic relationship.

9
10 7 10 9
6 6
5 1 8 5 1
4 2 4 2 8
3 3 7

1-Ethyl-1,3-dimethyl- 1-Ethyl-2,4-dimethyl-
cyclohexane cyclohexane

Naylor, S. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 189.

Cyclopropane and cyclobutane monoterpenoids (VS0300, VS0350)

These include the pyrethrin terpenoids such as Chrysamthemic acid, and
Grandisol the pheromone of the male boll weevil.

Iridoid, 10-alkyliridoid and secoiridoid monoterpenoids (VS0400,

VS0420, VS0440)
The iridoids and secoiridoids form a large group of plant constituents that are
found usually, but not invariably, as glycosides. Their biosynthesis has been
well established. C-11 is missing in some iridoids. The nitrogen-containing
iridoids and the large and important group of alkaloids derived from
Secologanin are described in the alkaloid section below.

11 7 11

6
6 4 4
5 3 5 3
7
9 2 10 9 2
8 1 O 1 O
8
10

Iridoid skeleton Secoiridoid skeleton

4,7-Dimethylcyclopenta[c]pyran, 9CI

Boros, C.A. et al. (1990) J. Nat. Prod., 53, 1055.

El-Naggar, L.J. et al. (1980) J. Nat. Prod., 43, 649.
Inouye, H. et al. (1986) Prog. Chem. Org. Nat. Prod., 50, 169.
Inouye, H. et al. (1991) Methods Plant Biochem., 7, 99.

74
Other cyclopentane monoterpenoids (VS0450)

This is a large group containing several carbon skeletons that probably arise
biogenetically by cleavage of bicyclic monoterpenoids.

Some cyclopentane monoterpenoid skeletons

Menthane monoterpenoids (VS0500, VS0520, VS0540)

The menthane group comprises three isomeric types, o-, m- and p-menthanes.
The p-menthanes are the most widespread and arise by a cyclisation of a regular
acyclic monoterpenoid. The o- and m- menthanes are much rarer, and
presumably arise by alkyl migration of p-menthanes. The numbering systems of
the menthanes reflect their biogenetic relationship. Since p-menthane has a
plane of symmetry the numbering of ring substituents is chosen to give the
lowest numbers consistent with the avoidance of compound locants for double
bonds when possible. For example the name p-menth-1-en-6-one is preferred to
p-menth-1(6)-en-2-one.
7 10 7

1 8 1
6 2 9 6 2
5 3 5 3 9
4 4 8

o-Menthane 10

m-Menthane
7

1
6 2
5 3 O
4

8
10 9

p-Menthane, 8CI
1-Methyl-4-(1-methylethyl)- p-Menth-1-en-6-one
cyclohexane, 9CI

Other cyclohexane monoterpenoids (VS0600)

Cyclohexane skeletons that are not included in previous groups are collected
here. They probably arise by cleavage of bicyclic monoterpenoids.

Other cyclohexane monoterpenoid skeletons

Cycloheptane monoterpenoids (VS0700)

This small group of compounds may arise by ring expansion of the p-menthane
skeleton.

75
 Cycloheptane monoterpenoid skeletons

Bicyclic monoterpenoids (VS0800–VS1050)

The bicyclic monoterpenoids arise biogenetically by further cyclisation of
monocyclic terpenoids followed by various rearrangements. They easily
undergo a wide variety of skeletal rearrangements and many may be artifacts
produced during isolation procedures. The numbering systems given below are
those most commonly used and follow the systematic (Von Baeyer) numbering
scheme, although particularly in the older literature several numbering systems
can be found, e.g. for the pinanes.
10
9 8
7
1
4 3 6 2
5 1 7
5 3 8
6 4
2
10 9

Camphane Fenchane
1,7,7-Trimethylbicyclo- 1,3,3-Trimethylbicyclo-
[2.2.1]heptane, 9CI [2.2.1]heptane, 9CI
VS0800 VS0850
10
2
1
7 9 3
8
6
4
5

Pinane
2,6,6-Trimethylbicyclo[3.1.1]heptane, 9CI
VS0900
10 10

3 4
4 2 3 5
5 1 2 1
6 6

7 7
8
9 9 8

Carane Thujane
3,7,7-Trimethylbicyclo- 4-Methyl-1-(1-methylethyl)-
[4.1.0]heptane, 9CI bicyclo[3.1.0]hexane, 9CI
VS0950 VS1000

Miscellaneous bicyclic monoterpenoids VS1050

Pelter, A. et al. (1969) in Rodd’s Chemistry of Carbon Compounds, 2nd edn. Elsevier,
Amsterdam, IIC, 136.

Tricyclic monoterpenoids (VS1200)

Tricyclene and Teresantalol are two examples of this small group of natural
compounds.

76
 Tricyclene
1,7,7-Trimethyltricyclo[2.2.1.02,6]heptane, 9CI

Sesquiterpenoids (VS1300–VS5320)
The sesquiterpenoids are C15 compounds formed by the assembly of three
isoprenoid units. They are found in many living systems but particularly in
higher plants. There is a large number of sesquiterpenoid carbon skeletons,
which all however arise from the common precursor, farnesyl pyrophosphate, by
various modes of cyclisations followed, in many cases, by skeletal
rearrangement.

Bryant, R. (1969) in Rodd’s Chemistry of Carbon Compounds, 2nd edn. Elsevier,

Amsterdam, IIC, 256.
Cane, D.E. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J.W. Porter et al.),
Wiley, New York, Vol. 1, p. 283.
Cane, D.E. (1990) Chem. Rev., 90, 1089.
Cordell, G.A. (1976) Chem. Rev., 76, 425.
Fraga, B.M. (1998) Nat. Prod. Rep., 15, 73
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 117.
Parker, W. et al. (1967) Quart. Rev. Chem. Soc., 21, 331.
Roberts, J.S. (1972) in Chemistry of Terpenes and Terpenoids, (ed. A.A. Newman)
Academic Press, London, p. 88.

Simple farnesane sesquiterpenoids (VS1300)

The simple farnesanes are named semi-systematically in this Dictionary
although the systematic trimethyldodecane naming is used extensively in the
literature. The farnesane numbering system is used as a biogenetic numbering
system for many sesquiterpenoid skeletons.
13 14 15

1
11 9 7 5 3
12 10 8 6 4 2

Farnesane
2,6,10-Trimethyldodecane, 9CI

Furanoid farnesane sesquiterpenoids (VS1320)

Although many numbering systems have been used for furanoid farnesanes,
such as Ngaione, it is logical to use the farnesane numbering system for this
group.

Irregular acyclic sesquiterpenoids (VS1400)

The various skeletons that are not clearly head to tail arrangements of
isoprenoid units may arise by rearrangement of a regular acyclic precursor or by
cleavage of a cyclic terpenoid structure such as a cembrane.

Some irregular acyclic sesquiterpenoid skeletons

77
Miscellaneous cyclobutane and cyclopentane sesquiterpenoids
(VS1420, VS1430)
This group contains a variety of miscellaneous cyclobutane and cyclopentane
sesquiterpenoids

Some miscellaneous cyclopentane sesquiterpenoid

skeletons

Cyclofarnesane and rearranged cyclofarnesane sesquiterpenoids

(VS1450, VS1460, VS1470)
Cyclofarnesanes arise by formation of a six-membered ring between carbons 6
and 11 of farnesane. They include Abscisic acid whose accepted numbering
system is ‘non-farnesane’. Methyl group migration gives the rearranged cyclo-
farnesane skeleton. The herbertianes, included in this group, (not to be confused
with herbertanes) are 5,10-cyclofarnesanes.

15 12 13
12 13
7
11 13 9 12
1 9 1 11
2 6 8 10 2 8 10 15
3 5 7 5 1
4 6 3
14 14 14 4 2

Cyclofarnesane Rearranged cyclofarnesane Herbertiane

1,1,3-Trimethyl-2-(3-methyl- skeleton 4-Methyl-2-(2-methylbutyl)-
pentyl)cyclohexane 1,2,4-Trimethyl-3-(3-methyl- 1-(1-methylethyl)cyclohexane
pentyl)cyclohexane

Milborow, B.V. et al. (1991) Methods in Plant Biochem., 7, 213.

Weyerstahl, P. (1992) Annalen, 1325

Bisabolane sesquiterpenoids (VS1500)

The bisabolanes are a fairly large group mainly found as constituents of higher
plants. The numbering system used for bisabolanes is the same as the farnesane
system. Since the cyclohexane ring has a plane of symmetry, substituents in this
ring should be numbered where possible avoiding the compound locant, 1(6),
for a double bond and keeping the numbers for the substituents in the
cyclohexane ring as low as possible.

14

7 5
8 6 4
9 1 3
2
10 15

13 11
12

Bisabolane
1-(1,5-Dimethylhexyl)-4-methylcyclohexane, 9CI

Cyclobisabolane sesquiterpenoids (VS1550)

This section includes the sesquicarane and sesquisabinane carbon skeletons
numbered in accordance with bisabolane.

78
 14
14
7
7 1
1
8 6 2 8 6 2
9 5 3 9 5 3
4 4
10 15 10 15
11 11
12 13 12 13

Sesquicarane Sesquisabinane
3,7-Dimethyl-7-(4-methyl- 1-(1,5-Dimethylhexyl)-
pentyl)bicyclo- 4-methylbicyclo[3.1.0]-
[4.1.0]heptane, 9CI hexane, 9CI

Elemane sesquiterpenoids (VS1600)

Elemanes are numbered consistently with eudesmanes (see below) and
germacranes. They are rapidly formed in vitro by Cope rearrangement of the
corresponding 1(10), 4-germacradienes and it is possible that they are artifacts
produced during the isolation procedures. Some elemanes are oxidatively
modified, e.g. Vernolepin which presumably is not formed by a Cope
rearrangement during isolation.
14
1 9
2 10 8
3 7 12
4 5 6 11

15 13

Elemane
1-Ethyl-1-methyl-2,4-bis-
(1-methylethyl)cyclohexane, 9CI

Germacranes (VS1650–VS1700)
The numbering of the germacrane skeleton poses a problem since there is a
plane of symmetry through carbons 2 and 7. Germacranes are normally drawn
in a conventional way as shown below with H-7 in the α-configuration. Care
should be taken with the small number of germacranes with a double bond at C-
7 as the ring can be numbered in either direction. Germacranes frequently have
double bonds in the 1(10) and 4 positions. There have been proposals to give
different names to the skeletons with (1(10)Z, 4E) (melampolides) and (1(10)E,
4Z) (heliangolides) configurations. However this is confusing and in DNP all
compounds are named as germacranes. A further problem with the represen-
tation of germacranes arises from substituents at carbons drawn as reentrant
angles. Wherever possible germacranes should be drawn without substituents at
reentrant centres as in this Dictionary, and care should be exercised when
reading the literature.
The large germacrane group is divided into simple germacranes, that is those
without a lactone or furan ring (VS1650), 12,6-germacranolides (VS1660),
12,8-germacranolides (VS1670), furanogermacranes, nor- and homo-
germacranes (VS1680), secogermacranes (VS1690) and cyclogermacranes
(VS1700).

2
1
10
9
8
O
8
3
14
7 H 12
4 5 6
11

15 13

Germacrane Furanogermacrane
1,7-Dimethyl-4-(1-methyl- 4,5,6,7,8,9,10,11-Octahydro-
ethyl)cyclodecane, 9CI 3,6,10-trimethylcyclodeca[b]-
furan, 9CI

79
Brown, D.S. et al. (1992) Heterocycles, 34, 807.
Fischer, N.H. et al. (1979) Prog. Chem. Org. Nat. Prod., 38, 47.
Fischer, N.H. (1990) Recent Adv. Phytochem., 24, 161.

Lepidozanes and bicyclogermacrane sesquiterpenoids (VS1710)

Bicyclogermacranes, found in higher plants, have a cis-fused cyclopropane ring
junction whereas the stereoisomeric lepidozanes from liverworts have a trans-
fused ring junction.
1 10 9
2 8
14
3 7
4 5 6
11
15 12
13

Bicyclogermacrane
3,7,11,11-Tetramethylbicyclo[8.1.0]undecane, 9CI

Humulane sesquiterpenoids (VS1720)

At least three numbering systems are in use for the humulane skeleton. In DNP
the farnesane numbering system has been chosen rather than those based on
germacrane numbering since the biosynthetic pathway to humulane does not
involve germacrane.
6 8 9
5 7
14 10
4
3 2 1 11
12
15 13

Humulane
1,1,4,8-Tetramethylcycloundecane, 9CI

Gonzaléz, A.G. et al., (1995), Prog. Chem. Org. Nat. Prod., 64, 1

Caryophyllane sesquiterpenoids (VS1730)

Further cyclisation of the humulane skeleton between carbons 2 and 10
produces the caryophyllane skeleton. Several numbering systems are in use for
caryophyllanes; the one chosen for DNP is that based on farnesane.
12

13 9 8
11 10
7 14
1 2 6
3 45

15

Caryophyllane
2,6,10,10-Tetramethylbicyclo[7.2.0]undecane, 9CI

Bicyclohumulane sesquiterpenoids (VS1740)

A small group of 7,9-cyclohumulanes is named as bicyclohumulanes.
8
9
6 7
5
14 10
4
3 2 1 11
12
15 13

Bicyclohumulane
1,5,8,8-Tetramethylbicyclo[8.1.0]undecane, 9CI

80
Cuparane sesquiterpenoids (VS1750)
Cuparane is formed by cyclisation between carbons 6 and 11 of the bisabolane
skeleton and the numbering system used here takes account of this fact.
Cuparanes are found in liverworts, higher plants and marine organisms.
14 8 9
4 5
15 3 6 10
7 11
2 1

12 13

Cuparane
(Most have an aromatic ring and are named in CA
as substituted benzenes)

Cyclolaurane sesquiterpenoids (VS1760)

Cyclolauranes found in marine organisms may be considered as cyclocuparanes
but as they co-occur with lauranes, the numbering system has been chosen to
agree with the accepted laurane system.
14 2 3
10 11
15 9 6 1 4
5
8 7
12
13

Cyclolaurane
1,2-Dimethyl-2-(4-methylcyclohexyl)bicyclo[3.1.0]hexane, 9CI

Herbertane sesquiterpenoids (VS1800)

Herbertanes are a small group of compounds isolated from liverworts and fungi.
As the biosynthesis of this skeleton is not known the numbering system
proposed in the literature is used.
13
2 1 8 9
3 6 7 10
11
4 5

14 15
12

Herbertane
(Mostly named as substituted benzenes in 9CI)

Laurane sesquiterpenoids (VS1850)

Lauranes are found in marine organisms, particularly Laurencia spp.
14 2 3
10 11
15 9 6 1 4
5 12
8 7

13

Laurane
(Mostly named as substituted benzenes in 9CI)

Trichothecane sesquiterpenoids (VS1900)

The biologically active trichothecanes are produced by various species of
imperfect fungi. Probably their most important biological activity is their
cytostatic action. Most trichothecanes contain a 12,13-epoxide grouping
(Scirpane) and for convenience many trichothecanes are named as derivatives of
the parent Scirpane in DNP.

81
 H H
16
10 O
9 11 1 2
8 6 12 3
7 5
13
15 4
14

Trichothecane, 9CI

A group of naturally occurring trichothecanes are macrocyclic lactones,

incorporating a bridge derived from mevalonic acid and acetate. An example is
Baccharinol.

Betina, V. (ed.) (1984) Mycotoxins: Production, Isolation, Separation and Purification,

Elsevier, Amsterdam, Vol. 8.
Grove, J.F. (1996), Prog. Chem. Org. Nat. Prod., 69, 1
Johann Wolfgang Goethe-universitaet (1984) Synform, 2 (synth).
Lacey, J. (1987) Trichothecenes and other Mycotoxins, Wiley, New York.
McDougal, P.G. et al. (1985) Prog. Chem. Org. Nat. Prod., 47, 153.
Steyn, P.S. (ed.) (1986) Mycotoxins and Phycotoxins, Elsevier, Amsterdam.
Ueno, Y. (ed.) (1983) Trichothecenes, Chemical, Biological and Toxicological Aspects,
Elsevier, Amsterdam.
Wylie, T. et al. (1977) Mycotoxic fungi, Mycotoxins and Mycotoxicoses, Dekker, New
York (3 vols).

Eudesmane sesquiterpenoids (VS1950–VS2000)

Eudesmanes are called selinanes in the older literature. The eudesmanes found
in higher plants generally have the stereochemistry shown below. ent-
eudesmanes are found in some species of liverworts. As with the germacrane
group, the eudesmanes are divided into groups comprising simple eudesmanes
(VS1950), eudesman-12,6-olides (VS1970), eudesman-12,8-olides and
furanoeudesmanes (VS1975), secoeudesmanes (VS1990), and noreudesmanes
(VS2000). There is also a large group of esters based on the dihydro-β-
agarofuran skeleton which are grouped separately (VS1980). Within the
eudesmane group, particularly with dihydro-β-agarofuran derivatives, there is
some confusion concerning the numbering of carbons 14 and 15. The
numbering given here should be adopted.
14
14
1 9 10
2 10 8
3 5 7 11 12 4
4 6
H 15
O
15 13

Eudesmane Dihydro-β-agarofuran
Decahydro-1,4a-dimethyl- 2,2,5,9-Tetramethyl-
7-(1-methylethyl)- 2H-3,9a-methano-
naphthalene, 9CI 1-benzoxepin, 9CI

Emmotin sesquiterpenoids (VS2010)

The emmotin group are 14(10 → 1)-abeoeudesmanes which have an aromatic
ring A and the methyl at C-10 migrated to C-1.
14

10

15

Emmotin skeleton

82
Oppositane sesquiterpenoids (VS2020)
The oppositanes are 8(7 → 6)-abeoeudesmanes and are found in plants and
marine organisms.
14
1 9
2 10
8
3 5 6
4
12
7
15 11

13

Oppositane
Octahydro-3a,7-dimethyl-1-(2-methylpropyl)-1H-indene, 9CI

Farfugin sesquiterpenoids (VS2040)

The farfugin group are 14(10 → 9)-abeoeudesmanes which have an aromatic
ring B and the methyl at C-10 migrated to C-9.
14

10

15

Farfugin skeleton

Cycloeudesmane sesquiterpenoids (VS2050)

Various cycloeudesmanes are included in this section.

Gorgonane sesquiterpenoids (VS2060)

The gorgonanes are derived from eudesmanes by isopropyl group migration to
C-6.

Gorgonane
Decahydro-1,4a-dimethyl-8-(1-methylethyl)naphthalene, 9CI

Eremophilane sesquiterpenoids (VS2100–VS2130)

The eremophilanes have been shown to be derived from eudesmanes by
migration of the methyl group at C-10 to C-5. There is confusion in the
literature about the numbering of carbons 14 and 15; the biogenetic numbering
given below should be used. The normal stereochemistry is shown, although
there are several exceptions to this. As with the other larger categories, the
eremophilanes are separated into simple eremophilanes (VS2100),
eremophilanolides and furanoeremophilanes (VS2110), seco- and
abeoeremophilanes (VS2120) and noreremophilanes (VS2130).

83
 H H
1 9 O
2 10 8
12
3 5 7 11 12
4 6
14
15 13 13

Eremophilane Furanoeremophilane
Decahydro-1,8a-dimethyl- 4,4a,5,6,7,8,8a,9-Octahydro-
7-(1-methylethyl)- 3,4a,5-trimethylnaphtho-
naphthalene, 9CI [2,3-b]furan, 9CI

Pinder, A.R. (1977) Prog. Chem. Org. Nat. Prod., 34, 82.

Chiloscyphane sesquiterpenoids (VS2140)

The chiloscyphanes, a small group isolated from liverworts, are 8(7 → 6)-
abeoeremophilanes.
1 9
2 10
8
3 5 6
4 12
14 7
11
15
13

Chiloscyphane
Octahydro-7,7a-dimethyl-1-(2-methylpropyl)-1H-indene, 9CI

Aristolane sesquiterpenoids (VS2150)

The aristolanes, isolated inter alia from Aristolochia spp., are 6,11-
cycloeremophilanes.
1 9
2 10 8
3 5 7
4 6
14 11
15 12
13

Aristolane
Decahydro-1,1,7,7a-tetramethyl-1H-cyclopropa-
[a]naphthalene, 9CI

Nardosinane sesquiterpenoids (VS2160)

The nardosinanes, isolated from marine organisms, are eremophilanes in which
the isopropyl group has migrated to carbon 6.
1 9
2 10 8
3 5 7
4 6
14
15 11
13 12

Nardosinane
Decahydro-1,8a-dimethyl-8-(1-methylethyl)naphthalene

Brasilane sesquiterpenoids (VS2170)

No biosynthetic scheme has been proposed for this skeleton.
15
14

9 2 13
1 3
8
7 6 4
5

10
11 12

Brasilane
Octahydro-1,6,6-trimethyl-4-(1-methylethyl)-1H-indene

84
Cacalol sesquiterpenoids (VS2180)
The cacalol sesquiterpenoids occur, inter alia, in Cacalia spp. and are
eremophilanes, typically with an aromatic ring B, in which carbon-14 has
further migrated to C-6.

1 9 8
2 10
5
3
4 6 7 11 12

15 14 13

Cacalol skeleton

Valerane sesquiterpenoids (VS2200)

The valeranes (also called jatamansanes), mainly from Valeriana spp., are
eudesmanes where the methyl group at C-4 has migrated to C-5. There is
normally a carbonyl group at C-4.
14
1 9
2 10 8
3 7
4
5
6 11 12

15
13

Valerane
Decahydro-4a,8a-dimethyl-2-(1-methylethyl)naphthalene

Miscellaneous rearranged eudesmane sesquiterpenoids (VS2220)

Various methyl-migrated eudesmanes are grouped together here. The methyl
groups should retain their numbering on migration.
14

15

14 15

Cadinane sesquiterpenoids (VS2250, VS2260)

The nomenclature, numbering and absolute stereochemistry of this group is
somewhat confused. Biogenetic (germacrane) numbering is used in DNP, but
many other numbering systems have been used in the literature. The names of
the skeletons depend on the relative stereochemistries at carbons 1, 6 and 7 as
indicated. Moreover, the aromatised skeletons are given different names,
calamenene and cadalene, and these are often given different numbering
systems. Nor-and seco-cadinanes are grouped separately (VS2260).

85
 14
H H
2 10
3 1 9
4 6 8
5 7
15
H H
11
13 12

Cadinane Muurolane
Decahydro-1,6-dimethyl-
4-(1-methylethyl)naphthalene, 9CI

H H

H H

Bulgarane Amorphane

Calamenene Cadalene

Bordoloi, M. et al. (1989) Phytochemistry, 28, 2007.

Alliacane sesquiterpenoids (VS2270)

The alliacanes from Marasmius alliacus and the aromatic primnatrienes from a
Primnoeides spp. have unfortunately been assigned different numbering
systems. The biosynthesis of this skeleton has not been established.
10

1 15
2 9 8 6
7 1
7 5 2
3 5 6 4 3
4 14

11
12 13

Alliacane Primnatriene
Octahydro-2,2,4-trimethyl-
7-(1-methylethyl)-
1H-indene, 9CI

Oplopane sesquiterpenoids (VS2280)

Oplopanes, from higher plants, are 3(4 → 5)-abeocadinanes and the numbering
system used here is biogenetic.
14

2 10
1 9
3
5 6 8
7

15 4 11
12 13

Oplopane
1-Ethyloctahydro-4-methyl-7-(1-methylethyl)-1H-indene

Mutisianthol sesquiterpenoids (VS2290)

This is a small group of 6(7 → 8)-abeocadinanes from Jungia and Mutisia spp.
Again the numbering system is biogenetic.

86
 14

2 10
3 1
9
4 6 8
5 12
15
7 11

13

Mutisianthol group skeleton

Octahydro-1,5-dimethyl-3-(2-methylpropyl)-1H-indene

Drimane sesquiterpenoids (VS2300)

The drimanes, from fungi and higher plants, arise by direct cyclisation of a
farnesane derivative. The accepted numbering system is shown. Compounds of
the ent- series such as Iresin were isolated earlier from Iresine spp. Nor- and
secodrimanes are grouped separately (VS2320).

11
15
12
1 9
2 10 8
3 5 7
4 6

13 14

Drimane
Decahydro-1,1,4a,5,6-pentamethylnaphthalene

Cordell, G.A. (1976) Chem. Rev., 76, 425.

Djerassi, C. et al. (1958) J. Am. Chem. Soc., 80, 2593.
Jansen, B.J.N. et al. (1991) Nat. Prod. Rep., 8, 309;319.

Coloratane sesquiterpenoids (VS2310)

The coloratanes, few in number, are related to the drimanes. A methyl migration
from C-4 to C-3 has occurred.

11
15
12
1 9
2 10 8
3 5 7
4 6
14

13
Coloratane
Decahydro-1,2,4a,5,6-pentamethylnaphthalene

Xanthane sesquiterpenoids (VS2380)

The xanthanes, originally isolated from Xanthium spp., are 4,5-secoguaianes.

14

2 10
3 1 9
4 5 8
6 7
15
11
12
13

Xanthane
1-Butyl-2-methyl-5-(1-methylethyl)cycloheptane

Carabrane sesquiterpenoids (VS2390)

The carabranes are a small group of 5,10-cycloxanthanes.

87
 14

2 10
3 1 9
4 5 8
6 7
15
11
12
13

Carabrane
7-Butyl-1-methyl-4-(1-methylethyl)bicyclo[4.1.0]heptane

Guaiane sesquiterpenoids (VS2400–VS2440)

This large group is divided into simple guaianes (VS2400), 12,6-guaianolides
(VS2410), 12,8-guaianolides (VS2420), guaiane dimers (VS2430), and seco-,
cyclo- and abeoguaianes (VS2440).
14

2 10
3 1 9
4 5 8
6 7
15
11
12
13

Guaiane
Decahydro-1,4-dimethyl-7-(1-methylethyl)azulene, 9CI

Fischer, N.H. et al. (1979) Prog. Chem. Org. Nat. Prod., 38, 47.
Fischer, N.H. et al. (1990) Recent Adv. Phytochem., 24, 161.

Pseudoguaiane sesquiterpenoids (VS2450, VS2470)

The migration of a methyl group of the guaiane skeleton from C-4 to C-5
produces the pseudoguaiane skeleton. There is often an oxygen function at C-4.
14

2 10
3 1 9
4 5 8
6 7
15
11
12
13

Pseudoguaiane
Decahydro-4,8a-dimethyl-7-(1-methylethyl)azulene

Fischer, N.H. et al. (1974) Prog. Chem. Org. Nat. Prod., 38, 47.

Aromadendrane sesquiterpenoids (VS2500)

The aromadendranes are 6,11-cycloguaianes. The smaller groups of 5,10-
cycloaromadendranes and seco-aromadendranes, including the plagiochilins
which are 2,3-secoaromadendranes, are listed separately (VS2520, VS2540).
14

2 10
3 1 9
4 5 8
6 7
15
11

13 12

Aromadendrane
Decahydro-1,1,4,7-tetramethyl-1H-cycloprop[e]azulene, 9CI

Gijsen, H.J.M. et al. (1995), Prog. Chem. Org. Nat. Prod., 64, 149

88
Cubebane and ivaxillarane sesquiterpenoids (VS2600, VS2620)
The small groups of cubebanes and ivaxillaranes are 1,6- and 8,10-
cycloguaianes respectively.
14 14

2 10 2
3 1 9 1 10 9
3
4 5 8 4 5 8
6 7 6 7
15 15
11 11
12 12
13 13

Cubebane Ivaxillarane
Octahydro-3,7-dimethyl-4-(1-methylethyl)-
1H-cyclopenta[1,3]cyclopropa[1,2]-
benzene, 9CI

Patchoulane and rearranged patchoulane sesquiterpenoids (VS2650,

VS2660)
Patchoulanes are 1,11-cycloguaianes. Various rearranged patchoulanes are also
found, in for example patchouli oil. Biogenetic numbering has been used here.

14 14 14

2 10 2 2 10 9
3 1 12 9 3 1 10 9 3 1 11 12
11
4 5 4 5 13 128 4 5
13 11 8 13 8
6 7 6 7 6 7
15 15 15

Patchoulane Rearranged patchoulanes

Valerenane sesquiterpenoids (VS2710)

Valerenanes are 8(7 → 6)-abeoguaianes. Only a few representatives have been
reported. They are not to be confused with the valeranes (see above).
14

2 10
1 9
3
4 5 6
8

7 12
15 11

13

Valerenane
Octahydro-1,4-dimethyl-7-(2-methylpropyl)-1H-indene

Africanane sesquiterpenoids (VS2750)

The farnesane numbering system is used for the africanane skeleton although
the biosynthesis has not been established conclusively. Some compounds (e.g.
Africanone) have been named as africananes but have since been shown to
have a different skeleton.
14

8
5 7
4 6 9
3 2 10
1 11
15 12
13

Africanane
Decahydro-3,3,5,7b-tetramethyl-1H-cycloprop[e]azulene

89
Lippifoliane and himachalane sesquiterpenoids (VS2760,
VS2780)
Many numbering systems have been used for the himachalane skeleton. The
farnesane system has been used here. The small group of lippifolianes are 7,9-
cyclohimachalanes.
14

4 5 7
6 8
3
15 2 1 9
11 10
13
12

Himachalane
Decahydro-2,5,9,9-tetramethyl-1H-benzocycloheptene, 9CI

Longipinane sesquiterpenoids (VS2800)

Longipinanes are 2,7-cyclohimachalanes. Several numbering systems have been
used for this skeleton, the farnesane system being used for consistency here.
The absolute configuration of this group is in some doubt.
14

4 5 7
6 8
3
15 2 1 9
11 10
13
12

Longipinane
2,6,6,9-Tetramethyltricyclo[5.4.0.02,8]undecane, 9CI

Longifolane sesquiterpenoids (VS2850)

Several numbering systems have been used in the older literature but as the
biosynthesis has been established, the biogenetic farnesane system is used here.

12 13

1 11
10
15
2 9
4 3
5 6 8
7

14

Longifolane
Decahydro-4,8,8,9-tetramethyl-1,4-methanoazulene, 9CI

Dev, S. (1981) Acc. Chem. Res., 14, 82.

Dev, S. (1981) Prog. Chem. Org. Nat. Prod., 40, 49.

Longibornane sesquiterpenoids (VS2900)

Longibornanes are 3,7-cyclohimachalanes.

14
8 9 1
7 10 7
6
6 11 3
1 5 15 5
2 3 13
4 12
15
Longibornane
Decahydro-4,5,5,8a-tetramethyl-1,4-methanoazulene, 9CI

90
Pinguisane sesquiterpenoids (VS3000)
The structures of several pinguisanes from liverworts have recently been
revised. Many of the trivial names in this group are confusing. The commonly
used numbering system is shown.
15
14
10
4 3
11 5 9
2
6 8 1
7

12 13

Pinguisane
5-Ethyloctahydro-1,3a,4,7a-tetramethyl-1H-indene

Thapsane and fukinane sesquiterpenoids (VS3050, VS3080)

The thapsanes occur in Thapsia spp. while fukinanes are found in Petasites
japonicus. Both types are relatively uncommon. One group of workers has
defined the thapsane skeleton as including an oxygen bridge, but that is not
followed here.
12
10
1 10 11
1 9
2
2 9 8 7 13
7 15 3 5
3 5 4 6 8
4 6
13 14
11 12 14 15

Thapsane Fukinane
Octahydro-1,2,3a,7,7,7a- Octahydro-2,3a,4-trimethyl-
hexamethyl-1H-indene 2-(1-methylethyl)-1H-indene

Picrotoxane sesquiterpenoids (VS3100)

The picrotoxanes are bitter, toxic constituents of the Orchidaceae. They are
generally highly oxygenated. The numbering system in general use seems to be
based on the menthane system and is inconsistent with the majority of other
schemes.
14
7

13 2
1 3
12
11 6 4 9
5 8

15 10

Picrotoxane
Octahydro-1,4,7a-trimethyl-5-(1-methylethyl)-1H-indene

Fischer, N.H. et al. (1979) Prog. Chem. Org. Nat. Prod., 38, 47.

Daucane sesquiterpenoids (VS3180)

Many numbering systems have been used for the daucanes; that chosen here is
related to the guaiane system. Daucanes are also called carotanes but this name
is not recommended because of possible confusion with the carotenoids.

91
 15

2 10
3 1 9
4 5 8
6 7 14
12 11

13

Daucane
Decahydro-3a,6-dimethyl-1-(1-methylethyl)azulene

Fraga, B.M. (1989) in Studies in Natural Products Chemistry, (ed. Atta-ur-Rahman)

Elsevier, Amsterdam, p. 721.
Ghisalberti, E.L. (1994), Phylochemistry, 37, 597.
Gonzaléz, A.G. et al. (1995), Prog. Chem. Org. Nat. Prod., 64, 1.

Isodaucane sesquiterpenoids (VS3190)

The isodaucanes (also called salviolanes) are clearly related to daucanes. The
numbering system used here is again related to the guaiane system.

15

2 10
3 1 9
4 5 8
11 6 7
12

13 14

Isodaucane
Decahydro-3a,7-dimethyl-1-(1-methylethyl)azulene

Perforane and pacifigorgiane sesquiterpenoids (VS3200, VS3350)

The perforanes form a small group found in Laurencia spp. Pacifigorgianes are
found in liverworts, higher plants and marine organisms.
15
12
5 7
4 6
1 8
2 10 3 1
11 9 2 9
3 14
4 5 8
6 7 15 13 10
14 11
13
12
Perforane
Decahydro-1,4,7,9a-tetra- Pacifigorgiane
methyl-1H-benzocyclo- Octahydro-1,5-dimethyl-
heptane 4-(2-methylpropyl)-1H-indene

Asteriscane sesquiterpenoids (VS3380)

The asteriscanes form a small group isolated from Asteriscus spp. The farnesane
numbering system is used here.

14

7 8
10 12
6 9
11
5 2
1 13
4 3

15

Asteriscane
Decahydro-2,2,4,8-tetramethyl-1H-cyclopentacyclooctene, 9CI

92
Illudane and protoilludane sesquiterpenoids (VS3400, VS3420)
Although historically different numbering systems have been proposed for the
illudane skeleton and the related groups, the biogenetic farnesane numbering is
shown here.
14
8 14
9 10 13 8
7 9 10 13
11 7
5 6 2 11
3 1 12 6 2
3 1 12
4 5
4
15 15

Illudane Protoilludane
Decahydro-2′,2′,4′,6′-tetra- Decahydro-3,6,6,7b-tetra-
methylspiro[cyclopropane- methyl-1H-cyclobut[e]-
1,5′-[5H]indene], 9CI indene, 9CI

Sterpurane sesquiterpenoids (VS3430)

Sterpuranes are biogenetically related to the illudanes. The farnesane numbering
system is used in preference to others.
14

8 10 13
5 7 9
4 11
6 2
3 1 12

15

Sterpurane
Decahydro-2a,5,5,7-trimethyl-1H-cyclobut[f]-
indene, 9CI

Illudalane sesquiterpenoids (VS3470)

The illudalanes are 4,6-secoilludanes and include the pterosins from bracken,
most of which have an aromatised ring.
14
8 10 13
7 9
11
6 2
3 1 12
4 5
15

Illudalane
5-Ethyloctahydro-2,2,4,6-tetramethyl-1H-indene, 9CI

Isolactarane, merulane, lactarane and marasmane sesquiterpenoids

(VS3470, VS3475, VS3480, VS3500)
These four groups are biogenetically related to the illudanes and the numbering
system used here reflects this fact. Numbering systems in the literature are
similar but care should be exercised with the numbering of the methyl groups.
14
14

8 7 8
9 10 13 9 10 13
7
5 11 5 6 11
6 2 2
3 1 12 4 1 12
3
4
15 15

Isolactarane Lactarane

14
14
8 7 8
9 10 13 9 10 13
7
11 5 11
6 2 2
3 1 12 6 1 12
3
5
4
4
15 15

Marasmane Merulane

93
Furodysin and furodysinin sesquiterpenoids (VS3550, VS3560)
A farnesane numbering system is used for the furodysin and the rearranged
furodysinin groups from Dysidea spp.
14 14
6 4 2 6 4
7 5 3 1 7 5 3
8 10 15 8 10 15 1
9 11 9 11 2

12 13 12 13

Furodysin skeleton Furodysinsin skeleton

3-Ethyldecahydro- 2-Ethyldecahydro-
1,1,6-trimethylnaphthalene 1,1,6-trimethylnaphthalene

Botrydial sesquiterpenoids (VS3600)

A non-biogenetic numbering system has been adopted for the botrydial group
from Botrytus spp.
10 15
14
11
1 8
2 9
7
3 5
4 6

13
12

Botrydial skeleton
Octahydro-1,1,3,3,4,5-hexamethyl-1H-indene

Spirovetivane sesquiterpenoids (VS3700)

Spirovetivanes (also known as vetispiranes) are found in vetiver oil and also
occur as phytoalexins in infected potatoes. The numbering system reflects their
eudesmane derivation.
14
1
2 10
3 5
4 9
6 8
7
15
11
13
12

Spirovetivane
6,10-Dimethyl-2-(1-methylethyl)spiro[4.5]decane, 9CI

Marshall, J.A. et al. (1974) Prog. Chem. Org. Nat. Prod., 31, 283.

Acorane sesquiterpenoids (VS3750)

The acoranes and the enantiomeric alaskanes have a symmetrical six-membered
ring. It has been suggested that C-2 should be chosen to be syn- to C-14.

14

5 6 10 9
15 4 1
3 2 7 8

11
12
13

Acorane
1,8-Dimethyl-4-(1-methylethyl)spiro[4.5]decane, 9CI

Marshall, J.A. et al. (1974) Prog. Chem. Org. Nat. Prod., 31, 283.

94
Chamigrane sesquiterpenoids (VS3800)
The chamigranes are a group of mainly marine natural products, mostly from
Laurencia and Aplysia spp. The numbering system is based on farnesane. There
are also some secochamigranes known (VS 3810).
12
13

10 11 5 4
9 6 3 15
8 7 1 2

14

Chamigrane
1,1,5,9-Tetramethylspiro[5.5]undecane, 9CI

Miscellaneous spirosesquiterpenoids (VS3850)

Some miscellaneous spirosesquiterpenoid skeletons are collected in this section.

1,2,5,9-Tetramethylspiro- 1,6-Dimethyl-8-(1-methyl-
[5.5]undecane ethyl)spiro[4.5]decane

Cedrane and isocedrane sesquiterpenoids (VS3900, VS3920)

The cedranes occur in wood oils and lac resins. Several numbering systems
have been used. The farnesane system is used here. Isocedranes are rearranged
cedranes; a related numbering system is in use.
15
14 15 14
4 4
5 3 5 3
7 1 7 1
8 6 2 8 6 2
9 10 11 9 10 11
13 13

12 12

Cedrane Isocedrane
Octahydro-3,6,8,8-tetra- Octahydro-3,4,8,8-tetra-
methyl-1H-3a,7-methano- methyl-1H-3a,7-methano-
azulene azulene

Zizaane and prezizaane sesquiterpenoids (VS3950, VS3960)

The zizaanes and prezizaanes are found in wood oils including vetiver oil.
13 13 14
14
15
4 5 6 4 5 6
7 15 7
3 3
1 8 1 8
2 11 2 11

10 9 10 9
12 12

Zizaane Prezizaane
Octahydro-3,7,8,8-tetra- Octahydro-3,7,7,8-tetra-
methyl-1H-3a,6-methano- methyl-1H-3a,6-methano-
azulene, 9CI azulene

Clovane sesquiterpenoids (VS4000)

Only one clovane is natural and it is possibly an artifact from the acid catalysed
rearrangement of a caryophyllene.

95
 14
15

12 7
6 8
11
5 1
10 9 13
4 2
3

Clovane
Decahydro-1,1,7-trimethyl-3a,7-methano-
3aH-cyclopentacyclooctene, 9CI

Precapnellane and capnellane sesquiterpenoids (VS4200, VS4250)

Precapnellanes and capnellanes are of marine origin. Capnellanes are 4,11-
cycloprecapnellanes.

13
12
5 4
7 6 15 14
3 9 8
8
9 10 2 10
1 7
11 1 11
2 6
4
3 5
12 15
14 13

Precapnellane Capnellane
Decahydro-1,5,8,8-tetra- Decahydro-3,3,4,7a-tetra-
methyl-1H-cyclopenta- methyl-1H-cyclopenta[a]-
cyclooctene pentalene, 9CI

Hirsutane and rearranged hisutane sesquiterpenoids (VS4300,

VS4310)
The hirsutanes are antibiotics from various fungi. Methyl migrated analogues
are also found.
8 8
6 7 9 10 6 7 9 10
5 3 2 11 12 5 3 2 11
4 1 4 1 12
14 13 14
15 15 13

Hirsutane Rearranged hirsutane

Decahydro-2,2,3b,4-tetra- Decahydro-2,3,3b,4-tetra-
methyl-1H-cyclopenta[a]- methyl-1H-cyclopenta[a]-
pentalene pentalene

Pentalenane sesquiterpenoids (VS4400)

The pentalenanes are antibiotics from Streptomyces spp. Also included in this
section are the rearranged and seco-pentalenanes.

14

14 1 1
8 7 8 7
2 6 13 15 2 6 13
4 4
15 3 5 3 5
10 9 10 9
11 12 11 12

Pentalenane Rearranged pentalenane

Decahydro-1,4,7,7-tetra- Decahydro-1,4,6,7-tetra-
methylcyclopenta[c]- methylcyclopenta[c]-
pentalene pentalene
Cane, D.E. et al. (1992) J. Org. Chem., 57, 844.

96
Silphinane, silphiperfoliane and presilphiperfoliane sesquiterpenoids
(VS4450, VS4460, VS4470)
These three groups are related biogenetically. The absolute configurations have
not been established unambiguously.
15
14 15
10 11 9 10 10
15 9 11 9 11
1 14 1
8 7 8 7 14
2 6 2 6 13 1
4 4 8 7
3 5 13 3 5 2 6
4
3 5 13
12 12
12
Silphinane Silphiperfoliane
Presilphiperfoliane
Decahydro-1,4,4,5a-tetra- Decahydro-1,4,5,6a-tetra-
methylcyclopenta[c]- methylcyclopenta[c]-
pentalene pentalene

Isocomane sesquiterpenoids (VS4500)

Several numbering systems have been used for this skeleton, including four
from one author. The originally proposed system is used here.

6 5
15 7 14
8
9 4
10 3 13
11 1 2

12

Isocomane
Decahydro-1,3a,4,6-tetramethylcyclopenta[c]pentalene

Panasinsane sesquiterpenoids (VS4630)

The panasinsanes from Panax ginseng are 2,7-cyclocaryophyllanes. The
farnesane numbering system is used here.

12
9
10 8
13 11
1 2 14
7
15 3 6
4 5

Panasinane
Decahydro-2,2,4a,8-tetramethylcyclobut[c]indene, 9CI

Modhephane sesquiterpenoids (VS4700)

The modhephanes form a small group of bridged tricyclic sesquiterpenes from
Isocoma wrightii. The numbering system originally proposed is used here.

14 15
9

2
1 8
3 10 7
5 6
4

13 11
12

Modhephane
Tetrahydro-1,1,3,4-tetramethyl-1H,4H-propanopentalene

Quadrane sesquiterpenoids (VS4750)

The quadranes are antibiotics from Aspergillus terreus.

97
 14 15

13
11 3
10 2
12 4
9 1
8 5

6
7

Quadrane

Campherenane, α-santalane and β-santalane sesquiterpenoids

(VS4770, VS4780, VS4790)
The campherenanes from Cinnamomum camphora and the α- and β-santalanes
from sandalwood oil (Santalum album) are biogenetically related. The farnesane
numbering system is used.

14 10 12
8 14 10 12
7 9 11 8
7 9 11
1 6
5 13 6
3 1
4 5 13
2 3
2 15 4
15

Campherenane α-Santalane
1,7-Dimethyl-7-(4-methyl- 2,3-Dimethyl-2-(4-methyl-
pentyl)bicyclo[2.2.1]- pentyl)tricyclo[2.2.1.02,6]-
heptane, 9CI heptane

1
15
4 2 12
3
6 7 9
5
11
8 10 13
14

β-Santalane
2,3-Dimethyl-2-(4-methylpentyl)bicyclo[2.2.1]heptane

Sativane sesquiterpenoids (VS4800)

The sativanes and their 13,14-seco-derivatives, the helminthosporanes, are
fungal metabolites from Helminthosporum sativum.
10 11 10 11
9 9

4 4
5 3 5 3
2 2
14 8 1 14 8 1
6 6
7 15 7 15
13 13

12 12

Sativane Helminthosporane
Octahydro-4,8-dimethyl-7- 1,6,7,8-Tetramethyl-4-
(1-methylethyl)-1,4-methano- (1-methylethyl)bicyclo-
1H-indene [3.2.1]octane

Copacamphane and sinularane sesquiterpenoids (VS4820, VS4850)

Copacamphanes and cyclocopacamphanes have regular farnesane skeletons and
a farnesane numbering system has been used. Sinularanes and
cyclocopacamphanes are rearrangement products.

98
 14 14
8 8
9 7 9 7
13 10 13 10
1 6 1 6
11 3 5 5
11 3
4 15 4
2 2
12 15 12

Copacamphane Cyclocopacamphane
Octahydro-4,8-dimethyl-7- Octahydro-1,7a-dimethyl-5-
(1-methylethyl)-1,4-methano- (1-methylethyl)-1,2,4-
1H-indene, 9CI metheno-1H-indene, 9CI

11 3 11 3
2 4 2 4
5 13 5 13
12 12
10 1 6 10 1 6

8 7 8 7
9 14 9 14

15 15

Sinularane Cyclosinularane
Octahydro-7a,8-dimethyl-5- Octahydro-1,4-dimethyl-7-
(1-methylethyl)-1,4-methano- (1-methylethyl)-1,2,4-
1H-indene, 9CI metheno-1H-indene, 9CI

Copaane sesquiterpenoids (VS4960)

Copaanes can either be considered as 5,10-cyclocadinanes or 1,6-
cycloeudesmanes.
14

2 10
3 1 9
4 6 8
5 7
15
11
12 13

Copaane
1,3-Dimethyl-8-(1-methylethyl)tricyclo[4.4.0.02,7]decane, 9CI

Ishwarane sesquiterpenoids (VS5000)

The ishwaranes form a small group of 10,12-cycloeremophilanes from
Aristolochia spp; 7,11- and 8,11-seco derivatives are known and are included in
this group.
9
1 10
2 13 8
3 5 12 11 7
4
6
14
15

Ishwarane
Decahydro-1,6,6a-trimethyl-1,2a-methano-
2aH-cyclopropa[b]naphthalene, 9CI

Rotundane sesquiterpenoids (VS5020)

The rotundanes are 10,12-cycloguaianes.
14

2 10 9
1 12
3 8
5 13 11
4 7
6

15
Rotundane
Decahydro-1,4,6-trimethyl-4,7-ethanoazulene, 9CI

99
Thujopsane sesquiterpenoids (VS5040)
Thujopsanes are found in higher plants whilst ent-thujopsanes are found in
liverworts. The biogenetic farnesane numbering system is used.
14

8 5
9 7 4
10 6 3
11
2 15
1
12 13

Thujopsane
Decahydro-2,4a,8,8-tetramethylcyclopropa[d]naphthalene, 9CI

Bourbonane sesquiterpenoids (VS5050)

Bourbonanes are 6,10-cycloguaianes. A guaiane numbering system is used.
14

2 1 10 9
3 8
5 6 7
4

11
15 13
12

Bourbonane
Decahydro-3a,6-dimethyl-1-(1-methylethyl)cyclobuta[1,3:3,4]-
dicyclopentene, 9CI

Gymnomitrane sesquiterpenoids (VS5070)

Gymnomitranes are biogenetically related to cuparanes. A farnesane numbering
system is used here.
15 12

3 2 11 10
4 1 9
5 6 7 8

14 13

Gymnomitrane
Decahydro-3a,4,7,8a-tetramethyl-4,8-methanoazulene, 9CI

Miscellaneous sesquiterpenoids (VS5090–VS5320)

Sesquiterpenoid skeletons that do not fit easily into the above categories are
collected here. They are divided into monocyclic, bicyclic, tricyclic and
tetracyclic sesquiterpenoids.

100
Diterpenoids (VS5350–VS7340)
The diterpenoids constitute a large group of compounds derived from
geranylgeranyl pyrophosphate. They are found in higher plants, fungi, insects
and marine organisms.

Hanson, J.R. (1971) Prog. Chem. Org. Nat. Prod., 29, 395.
Hanson, J.R. (1972) in Chemistry of Terpenes and Terpenoids, (ed. A.A. Newman)
Academic Press, London, p. 155.
Hanson, J.R. (1998) Nat. Prod. Rep., 15, 93.
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 124.
West, C.A. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J. W. Porter et al.)
Wiley, New York, Vol. 1, p. 375.

Phytane diterpenoids (VS5350)

Phytanes are regular acyclic diterpenoids. The phytane numbering system is
shown here.
17 18 19 20

13 9 5 1
15 11 7 3
16 14 12 10 8 6 4 2

Phytane
2,6,10,14-Tetramethylhexadecane

Prenylbisabolane and 10,15-cyclophytane diterpenoids (VS5380,

VS5390)
The prenylbisabolanes arise by cyclisation between carbons 1 and 6 of the
phytane skeleton. They retain their phytane numbering system. The 10,15-
cyclophytanes are important compounds including the retinal group. Since
10,15-cyclophytanes resemble carotenoids, a carotenoid-like numbering system
has usually been adopted. It is possible to view 10,15-cyclophytanes as 9,10-
secolabdanes and some are named and numbered as such in the literature.
19 18 17

9 13
1 7 11 15
2 6 8 10 12 14 16
3 5
4
20

Prenylbisabolane
1-Methyl-4-(1,5,9-trimethyldecyl)cyclohexane

16 17 19 20

7 11 15
1 9 13
2 6 8 10 12 14
3 5
4
18

10,15-Cyclophytane
1,1,3-Trimethyl-2-(3,7-dimethylnonyl)cyclohexane

Labdane and halimane diterpenoids (VS5400–VS5470)

Labdanes form a large group and occur in both enantiomeric series. The
halimanes are derived from labdanes by migration of the C-20 methyl group to
C-9. Nor-, seco- and rearranged labdanes, including the gnaphalanes, are
presented in separate sections.

101
 12 14 12 14 12 14
13 13 13
11 11 11 15
15 20 15
20 17 H 17 20 17
1 9 16 1 9 16 1 9 16
2 10 8 2 10 8 2 10 8
3 5 7 3 5 7 3 5 7
4 6 4 6 4 6

19 18 19 18 18 19

Labdane Halimane Gnaphalane

Decahydro-1,1,4a,6-tetra- Decahydro-1,1,5,6-tetra-
methyl-5-(3-methyl- methyl-5-(3-methyl-
pentyl)naphthalene, 9CI pentyl)naphthalene

Colensane and clerodane diterpenoids (VS5480–VS5530)

Colensanes are a small group of 4(3 → 2) abeolabdanes. Clerodanes arise from
labdanes by two methyl migrations. They are abundant and are found
particularly in Teucrium spp. where they are highly oxygenated. In the past ent-
clerodanes have been named as neoclerodanes and kolavanes but these names
are not widely used.
12 14 12 14
13 13
11 15 11 20 15
20 17 H 17
9 16 1 9 16
1 10 8 2 10 8
3 2
4 5 6
7 3
4
5
6
7

19 18 19
18
Colensane ent-Clerodane
Octahydro-1,1,2,3a,5- Decahydro-1,2,4a,5-
pentamethyl-4-(3-methyl- tetramethyl-1-(3-methyl-
pentyl)-1H-indene pentyl)naphthalene, 9CI

Merritt, A.T. et al. (1992) Nat. Prod. Rep., 9, 24.

Piozzi, F. et al. (1987) Heterocycles, 25, 807.
Rodriguez-Hahn, L. et al. (1994), Prg. Chem. Org. Nat. Prod., 63, 107.
Rodriguez-Hahn, L. et al. (1995), Recent Adv. Phytochem., 29, 311.

Abietane diterpenoids (VS5550–VS5600)

Abietanes may arise from pimaranes by migration of the methyl group at C-13.
This large group is divided into sections including furanoabietanes (VS5560),
secoabietanes and secofriedoabietanes (VS5570), nor- and homoabietanes
(VS5580), abeoabietanes (VS5590) and abietane dimers (VS5600).
16

12 15
11 13 17
20 H 14
1 9
2 10 8
3 5 7
4 6

19 18

Abietane
Tetradecahydro-1,1,4a-trimethyl-7-(1-methylethyl)-
phenanthrene, 9CI
San Feliciano, A. (1993), Planta Med., 59, 485.

13,16-Cycloabietane and 17(15 → 16)-abeoabietane diterpenoids

(VS5620, VS5630)
These groups include the coleons, lanugones and plectranthones from Coleus
and Plectranthus spp. Included in each group are the corresponding 19(4 → 3)-
abeo derivatives.

102
 16 16
15 15
12 12
11 13 17 11 13 17
20 14 20 14
1 9 1 9
2 10 8 2 10 8
3 5 7 3 5 7
4 6 4 6
19
19 18
18
13,16-Cycloabietane
19(4→3)-Abeo-13,16-cyclo-
abietane
15 15 17
17
12 12
11 13 16 11 13 16
20 14 20 14
1 9 1 9
2 10 8 2 10 8
3 5 7 3 5 7
4 6 4 6
19
19 18
18
17(15→16)-Abeoabietane
17(15→16),19(4→3)-
Tetradecahydro-1,1,4a-
Bisabeoabietane
trimethyl-7-propyl-
Tetradecahydro-1,2,4a-
phenanthrene
trimethyl-7-propyl-
phenanthrene

Totarane and nagilactone diterpenoids (VS5650, VS5660)

The totaranes may arise from abietanes by migration of the isopropyl group
from C-13 to C-14. They normally have an aromatic ring C and are found in
several species of higher plants. The nagilactone group are seconortotaranes
found in Podocarpus spp.
12
11 13 O
20 14 16
1 9 15 12
2 10 8 O
3 5 7 20 14 16
4 6 17 15

19 18
17
Totarane 19 18
Tetradecahydro-1,1,4a-
trimethyl-8-(1-methylethyl)- Nagilactone skeleton
phenanthrene
Bendall, J.G. et al. (1995) Aust. J. Chem., 48, 883.

Pimarane, rosane, erythroxylane, parguarane, devadarane and

isopimarane diterpenoids (VS5700–VS5770)
The pimaranes (VS5700) and isopimaranes (VS5750) (formerly called
sandaracopimaranes) arise by further cyclisation of the labdane skeleton.
Pimaranes have the ethyl group at C-13 syn- to the methyl group at C-10
whereas in the isopimaranes they are anti-. Both pimaranes and isopimaranes
occur in both enantiomeric series. Rosanes (VS5710) arise by migration of the
C-10 methyl group of pimaranes to C-9. 13-epi-Rosanes, e.g. Rimuene arise in
a similar manner from isopimaranes. Erythoxylanes (VS5720), parguaranes (VS
5730) and devadaranes (VS5740) represent a further degree of rearrangement of
pimaranes and isopimaranes.
17 16 16
17
12 12
11 13 15 11 13 15
20 14 H 9 14
1 9 1
2 10 8 2 10 20 8
3 5 7 3 5 7
4 6 4 6

19 18 19 18

Pimarane Rosane
7-Ethyltetradecahydro- 7-Ethyltetradecahydro-
Isopimarane
1,1,4a,7-tetramethyl- 1,1,4b,7-tetramethyl-
phenanthrene phenanthrene

103
 17 16 16 16
17 17
12 12 12
11 13 15 11 13 11 13
H 9 14 20
15
H 15
14 9 14
1 1 9 1
2 10 20 8 2 10 8 2 10 20 8
3 5 7 3 5 7 3 5 7
4 6 4 6 4 6
19
18 19 19
18 18
Erythroxylane Parguarane Devadarane
7-Ethyltetradecahydro- 5-Ethyltetradecahydro- 8-Ethyltetradecahydro-
1,4b,7,10a-tetramethyl- 1a,5,7b-trimethyl-1H- 3a,8,10a-trimethyl-
phenanthrene cyclopropa[a]phenanthrene cyclopropa[j]phenanthrene

Cassane and vouacapane diterpenoids (VS5800)

The cassanes presumably arise by methyl migration in the pimarane skeleton
from C-13 to C-14. The Erythrophleum alkaloids are simple derivatives of
cassanes and are listed in this section as well as in the Alkaloid section.
Furanocassanes are called vouacapanes.
15
12 O
11 13 16
20 H 14
1 9
2 10 8 17
3 5 7 20 H
4 6
17
19 18

Cassane 19 18
7-Ethyltetradecahydro-
1,1,4a,8-tetramethyl- Vouacapane skeleton
phenanthrene

Cleistanthane and isocleistanthane diterpenoids (VS5850)

The cleistanthane skeleton arises from pimaranes or isopimaranes by the
migration of the ethyl group from C-13 to C-14. Isocleistanthane is a 2(4 → 3)-
abeocleistanthane.
17
12
11 13
17
20 14 12
16
1 9 20 11 13
2 10 8 15 14 16
3 5 7 9
4 6 1 10 8
2 15
3 5 7
19 18 6

4
Cleistanthane 19
7-Ethyltetradecahydro- 18
1,4,4a,7-tetramethyl- Isocleistanthane skeleton
phenanthrene

Isocopalane and spongiane diterpenoids (VS5950)

Isocopalanes and spongianes are of marine origin and both have the same
carbon skeleton. A spongiane or spongian is a 15,16-epoxyisocopalane.

16
12
11 13
20 17 14 12
11 13 16
2
1
10
9
8
15 20 17 14 15 O
1 9
3 5 7 2 10 8
4 6
3 5 7
4 6
19 18
19 18
Isocopalane
Tetradecahydro-1,1,4a,7,8,8a- Spongiane skeleton
hexamethylphenanthrene

104
Podocarpane diterpenoids (VS5980)
Miscellaneous podocarpane derivatives that cannot be easily classified are
collected in this section.

Kaurane and phyllocladane diterpenoids (VS6000–VS6040)

The kauranes arise by further cyclisation of a pimarane cation intermediate
followed by rearrangement. Most kauranes occur in the ent-series. The less
common phyllocladanes have the methylene bridge on the opposite side from
the methyl at C-10. Nor-, seco- and rearranged kauranes are placed in separate
sections. The seco-kaurane group includes the Rabdosia constituents, e.g.
Enmein. Care should be taken when using Chemical Abstracts for this skeleton
as ent-kaurane is taken as the stereoparent and is named kaurane; 19-substituted
ent-kauranes are named as having a (4α)-18-substituent and phyllocladanes are
named as (5α,9α,10β)-kauranes. CA also uses Enmein as a basis for naming
some of the secokauranes.

12 12
11 13 17 11 13 17
20 20
9 14 16 9 14 16
1 1
2 10 8 15 2 10 8 15
3 5
H 7 3 5 7
4 6 4 6

19 18
H 19 18

ent-Kaurane Phyllocladane
≡ Kaurane, 9CI ≡ 5α,9α,10β-Kaurane, 9CI

Alhazimi, H.M.G. et al. (1994), J. Chem. Soc. Pak., 16, 193.

Fujita, E. et al. (1984) Prog. Chem. Org. Nat. Prod., 46, 77.

Beyerane diterpenoids (VS6050)

Beyeranes are formed by cyclisation of a pimarane cation intermediate without
rearrangement. Most beyeranes belong to the ent-series. ent-Beyerane is also
known as stachane. Chemical Abstracts names ent-beyeranes as 13-methyl-17-
norkauranes.
17
12
11 13
20
9 14 16
1
2 10 8 15
3 5
H 7
4 6

19 18
H

ent-Beyerane

Villanovane, atisane, trachylobane and helvifulvane diterpenoids

(VS6080, VS6100, VS6150, VS6160)
Rearrangement of the beyerane cation intermediate produces the villanovane
and atisane skeletons. Rearrangement of the beyerane cation intermediate
followed by cyclisation leads to the trachylobane and helvifulvane skeletons.
These skeletons are mostly found in the ent-series. ent-Atisane and ent-
trachylobane are named in CA as atisane and trachylobane (see remarks under
kaurane, above).

105
 15 12 17
17 16
12 11 13
16 11 13 20
20 9 H 14 9 14 15
1 1
2 10 8
3 5
2 10
5
H 8
7 3 7
4 6 4 6

18 19
H 18 19H

ent-Villanovane ent-Atisane
Tetradecahydro-4,4,8,11b- ≡ Atisane, 9CI
tetramethyl-9,11a-methano-
11aH-cyclohepta[a]-
naphthalene, 9CI

12 12
17 17
11 11 13
20 13 16 20 14
16
9 14
15 H 15
1 1 9
2 10 8 2 10 8
5
H
3 7 3 5 7
4 6 4 6

18 19
H 18 19
H

ent-Trachylobane ent-Helvifulvane
≡ Trachylobane, 9CI Tetradecahydro-4,4,7a,9b-
tetramethyl-8,8a-methano-
9aH-cyclopropa[b]-
phenanthrene, 9CI

Fraga, B.M. (1994), Phytochem. Anal., 5, 49 (Trachylobanes)

Aphidicolane diterpenoids (VS6180)

This small group includes the biologically active Aphidicolin and the Stemodin
type from Stemodia maritima. The methano-bridge stereochemistry is opposite
in Aphidicolin and Stemodin.
17
15
16
14 11
12
20 H
1 9 13
2 10 8
3 5 7
4 6

19 18

Aphidicolane
4,4,17-Trimethyl-9,15-cyclo-C,18-dinor-
14,15-secoandrostane

Gibberellins (VS6200)
The gibberellins, important plant hormones, are based on the ent-gibberellane
skeleton. They are produced by higher plants and the rice plant infecting fungus
Gibberella fujikuroi. They have also been isolated from red and green algae.
The biosynthesis of the gibberellins has been well studied and it is clear that
they are derived from ent-kaurene. In CA they are named as derivatives of the
stereoparent gibbane, which is a C15 skeleton and has a completely different
numbering scheme. Many of the natural gibberellins are C19 norditerpenes.
20 H
1 11 4 5
2 10 9 12 3 4a 4b 6
3 5 8 13 2 10a 9a 7
4 6 14 1 10 11
H 15 16 H 9 8
19 18 7
17

ent-Gibberellane Gibbane, 9CI

Bakker, H.S. et al. (1974) Tetrahedron, 30, 3631 (biosynth).

Beale, M.H. et al. (1990) Methods Plant Biochem., 24, 203 (rev).
Bearder, J.R. et al. (1976) J. Chem. Soc., Chem. Commun., 834 (biosynth).

106
Bearder, J.R. et al. (1977) Biochem. Soc. Trans. 5, 569 (rev).
Binks, R. et al. (1969) Phytochemistry, 8, 271 (ms).
Ceccarelli, N. et al. (1983) Phytochemistry 22, 2203 (biosynth).
Crosier, A. et al. (1970) Can. J. Bot., 48, 867 (biochem).
Evans, R. et al. (1970) J. Chem. Soc. C, 2601 (biosynth).
Evans, R. et al. (1975) J. Chem. Soc., Perkin Trans. 1, 1514 (cmr).
Hanson, J.R. (1965) J. Chem. Soc., 5036 (pmr).
Hanson, J.R. (1990) Nat. Prod. Rep., 7, 41 (rev).
Kamiya, Y. et al. (1983) Phytochemistry, 22, 681 (biosynth).
Lang, A. et al. (1970) Annu. Rev. Plant Physiol., 21, 537 (rev).
MacMillan, J. et al. (1970) Aspects Terpenoid Chem. Biochem., Proc. Phytochem. Soc.
Symp., 2nd, 153 (rev).
Mander, L.N. et al. (1988) Nat. Prod. Rep., 6, 541 (synth).
Mander, L.N. et al. (1992) Chem. Rev., 92, 573 (synth).
Phinney, B.O. et al. (1990) Recent Adv. Phytochem., 24, 203 (rev).
Takahashi, N. et al. (1969) Org. Mass Spectrom., 2, 711 (ms).
West, C. (1969) Biochem. J., 114, 3P (rev).
Yamaguchi, I. et al. (1975) J. Chem. Soc., Perkin Trans. 1, 992 (cmr).
Yamane, H. et al. (1977) Phytochemistry, 16, 831 (biosynth).

Leucothol and grayanotoxane diterpenoids (VS6220, VS6300)

The leucothol group and the grayanotoxins are also rearrangement products of
the ent-kaurane skeleton.
20 20
H H 3
2 H
2 10 11 1 10 11
3 1 9 12 4 9 12
18 5
4 6 8 13 8 13
18 5 7 14 6 7 14
19
19 15 16 15 16
17 17

Leucothol skeleton Grayanotoxane, 9CI

Cembrane diterpenoids (VS6400–VS6410)

The cembranes form a large group of diterpenoids found in higher plants (e.g.
tobacco and conifers), insects and marine organisms. The cembrane nucleus has
a plane of symmetry and is conventionally drawn with C-7 at the top as defined
by the C-1, C-8 axis, C-7 being chosen as bearing a double bond or equivalent.
The numbering system shown is generally accepted. Many polycyclic
diterpenoids can be regarded as formally arising by cyclisation of the cembrane
skeleton (or the related casbane skeleton – see below). As with germacranes,
care is necessary in interpreting published configurations at centres involving
reentrant angles.

18

6 4 16
5
7 3 2
8
19 1
15
9 13
10 12 14 17
11

20

Cembrane
1,7,11-Trimethyl-4-(1-methylethyl)cyclotetradecane, 9CI

Tius, M.A. (1988) Chem. Rev., 88, 719.

Wahlberg, I. et al. (1992) Prog. Chem. Org. Nat. Prod., 59, 141; 60, 1.
Weinheimer, A.J. et al. (1979) Prog. Chem. Org. Nat. Prod., 36, 285.

107
Rearranged cembrane diterpenoids (VS6420)
This group contains assorted, unusual macrocyclic diterpenoids including a
basmane derivative which is formally a (2,12 : 7,11) cyclised cembrane.
18

5 4 16
6 3
19 7 15

8 11 12 2 1 17
9 10 13 14
20

Basmane

Eunicellane and asbestinane diterpenoids (VS6440, VS6450)

These are marine natural products. The eunicellane (cladiellane) skeleton is
formally a 5,14-cyclocembrane and the cembrane numbering system is
preferred. The closely related asbestinane group has been assigned a different
numbering system.
18 19 19

20
4 6 7 8 11 9 8 7
3 5 9 12 10 6
20 18
2 14 12 10 13 1 3 5
1 13 11 14 2 4

15 15
16 17 16 17

Eunicellane Abestinane

Sphaerane diterpenoids (VS6460)

The bromosphaerol group of marine natural products contains an unusual
carbon skeleton. The numbering system is as shown. Bicyclic (lacking the 1, 10-
bond) and tetracyclic (with a 2,17-bond) derivatives are known. (N.B.
Sphaeranes are not to be confused with sphaeroanes, see below).

16
12
11 13
15
9 14
1
2 10 8
3 5 7
4 6

17
18
19 20

Sphaerane
Tetradecahydro-5,8a,10a-trimethyl-1-(1-methylethyl)-
phenanthrene

Briarane diterpenoids (VS6470)

The briaranes are marine diterpenoids with the numbering system as shown. The
carbon skeleton is formerly a 3,8-cyclocembrane.

15
16
14 2 4
13 1 3 5
12 10 9 6
11 7
8

20 19 17

18

Briarane

108
Dolabellane and modified dolabellane diterpenoids (VS6500, VS6510)
Dolabellanes are found in marine organisms and in liverworts. Several
numbering systems have been used in the literature. We have used the one
shown. The modified dolabellane group includes the neodolabellanes in which a
methyl has migrated from C-1 to C-11. A rare 3,9-cyclodolabellane is also
included in this group.
20 20

19 15 19
18 18
17 9 10 17 9 10
8 12 8 11 12
11
13 13
7 1 14 7 1 14
6 3 2 6 3 2
5 15 5
4 4

16 16

Dolabellane Neodolabellane

Dolastane and modified dolastane diterpenoids (VS6540, VS6550)

The name clavularane was originally used for this group of marine natural
products but now dolastane appears to be widely accepted. Dolastane is a 3,8-
cyclodolabellane but a different numbering system is used. The modified
dolastane group contains 8,9-secodolastanes and a chromophycane, a new
skeletal type related to dolastane by migration of the methyl C-20 to C-13.
18

19
17
16
6 7
8 9
4 10
5 12
14 13 11
3
2 1 20

15

Dolastane
Tetradecahydro-3a,5,8a-trimethyl-1-(1-methylethyl)-
benz[f]azulene, 9CI

Cyathane diterpenoids (VS6560)

The cyathanes are fungal metabolites. The biosynthesis of this unusual skeleton
has been studied. The accepted numbering system is as shown.

17

1 8
9 7
2
3 4 6
5 14
18 16
19 10 13
11 12
20

15

Cyathane
Tetradecahydro-3a,5a,8-trimethyl-1-(1-methylethyl)-
cyclohept[e]indene

Turner W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Sphaeroane diterpenoids (VS6570)

The sphaeroanes are marine algal products with a skeleton which is formally a
2,7-cyclodolabellane though the numbering system is different from that of
dolabellanes.

109
 20

17 19
18
6 5
4 3
16 7 2
10 1
8 9
14
11
13 12

15

Sphaeroane
Dodecahydro-3a,6,9-trimethyl-3-(1-methylethyl)-
benz[e]azulene, 9CI

Verrucosane and modified verrucosane diterpenoids (VS6580,

VS6590)
Verrucosanes and their modifications, including neoverrucosanes,
homoverrucosanes (3,5-secoverrucanes) and homoneoverrucosanes (2,4-
seconeoverrucosanes) are liverwort natural products. The tetracyclic
verrucosane skeleton is formally related to dolabellane by 4,10- and 6,8-bond
formation. A different numbering system from that of dolabellane is used. The
isomeric neoverrucosane has the cyclopropane bridging C-2 and C-3.

17 17

16 15 16 15

13 12 3 13 12
18 H 11 H 11
2 14 18 2 14
3 1 10 4 1 10
4 20 20
5 7 9 5 7 9
6 8 6 8
19 19

Verrucosane Neoverrucosane
Tetradecahydro-3a,5a,7a-trimethyl-
1-(1-methylethyl)cyclopenta-
[a]cyclopropa[g]naphthalene, 9CI

17 17

15 16 15
16
18 13 12 13 12
H 11 H 11
3 2 14 3 2 14
1 10 1 10
4 20 18 4 20
7 9 7 9
5 6 8 5 6 8
19 19

Homoverrucosane Homoneoverrucosane

Casbane diterpenoids (VS6600)

The casbane skeleton is closely related to cembrane and it seems logical to use
the cembrane numbering system although many others have been used in the
literature. Casbane, like cembrane, is the formal parent of several important
groups of diterpenoids especially from the Euphorbiaceae and Thymelaeceae.
Berdimerane has a rearranged casbane skeleton.
18
16
5 4
17
7 6 3 2 15
19 8 1
9 10 13 14
11 12

20

Casbane
3,7,11,15,15-Pentamethylbicyclo[12.1.0]pentadecane, 9CI

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

110
Jatrophane and 9,13-cyclojatrophane diterpenoids (VS6610, VS6620)
Jatrophane is the parent skeleton of a group of macrocyclic diterpenoids from
Euphorbia species. Formally it can be derived from casbane by 6,10-cyclisation
and opening of the cyclopropane. The numbering system shown is used fairly
consistently in all the related diterpenoids of this series. Two examples of the
9,13-cyclojatrophane skeleton have been isolated.

20

14 13 19
1 15
16 2
3 4 17 12 11 18
10
5 6
9
7 8

Jatrophane

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

Lathyrane diterpenoids (VS6650)

Derivatives of the lathyrane skeleton occur widely in the Euphorbiaceae as
mixed esters. Lathyrane is formally a 6,10-cyclocasbane. There is some
confusion in the literature over the configuration of the methyl group attached to
C-13. Reentrant angles should be avoided if possible.

20

14 13
1 12 19
15 17 11
16 2
3 4 9 10
5 6 18
7 8

Lathyrane
Tetradecahydro-1,1,3,6,9-pentamethyl-1H-cyclopenta[a]-
cyclopropa[f]cycloundecene

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

Rhamnofolane and daphnane diterpenoids (VS6660, VS6680)

The rhamnofolane and daphnane skeletons are closely related, being formally
derived from casbane by two cyclisations (6,10 and 5,14) followed by cleavage
of the 1,15 (daphnane) or 2,15 (rhamnofolane) cyclopropane bonds. Note that in
Chemical Abstracts, Daphnane is an alkaloidal stereoparent. Terpenoid
daphnane derivatives are named as derivatives of Daphnetoxin.
16

12 13 15
18 16 17
11
14 15 18 12 13
11
9 14
1 8
10 17
19 2 7 9 8
3 4 1 10
5 6 19 2 7
3 4
5 6
20
20
Rhamnofolane
Daphnane

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

Tigliane and ingenane diterpenoids (VS6700, VS6710)

The tigliane nucleus is formerly derived from casbane by 6,10- and 5,14-
cyclisations. This is the carbon framework of phorbol whose derivatives occur

111
widely in the Euphorbiaceae and are renowned for their tumour promoting and
irritant activity. The ingenane skeleton is derived by rearrangement of tigliane.
Ingenane esters also have irritant properties.
17
17 16
12 13 15
18
11 15 16 12 13 14
H 14 11
18
9 8 9 8
1 10 1 10
19 2 7 19 2 7
3 4 3 4
6
5 5 6

20 20

Tigliane Ingenane
Tetradecahydro-1,1,3,6,8- Dodecahydro-1,1,4,7,9-
pentamethyl-1H-cyclo- pentamethyl-1H-2,8a-
propa[3.4]benz[1,2-e]- methanocyclopenta[e]-
azulene, 9CI cyclopropa[e]cyclo-
decene, 9CI

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

Jatropholane and secojatropholane diterpenoids (VS6720)

Jatropholanes arise by 5,13- and 6,10-cyclisation of casbane. Subsequent
cleavage of the 2,15-cyclopropane bond affords crotofolane. Only a few
examples of these skeletons have been reported.

18 11 12 18 11 12
10 13 10 13
16
14 15 14
1 8 1 8 16
9 7 17 9 7
19 2 19 2 15
3 4 6 3 4 6
5 5
20 20 17

Jatropholane Crotofolane
Hexadecahydro-1,1,2,5,7- Tetradecahydro-2,5,10-
pentamethyl-6H-cyclohept- trimethyl-6-(1-methyl-
[1,2-e]indene ethyl)cyclohept[e]-
indene, 9CI

Evans, F.J. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 1.

Fusicoccane diterpenoids (VS6750)

Fusicoccanes occur in fungi and liverworts. Biosynthetic evidence favours the
involvement of a dolabellane-like precursor. The accepted numbering system
differs from that of dolabellane.
19
20
18
17 8 9
7 10 14
13
6 11 12
5 2 1
4 3 15

16

Fusicoccane
Tetradecahydro-1,4,9a-trimethyl-7-
(1-methylethyl)dicyclopenta[a,d]-
cyclooctene, 9CI
Krasnopolskaya, L.M. (1994), J. Plant Growth Regulation, 13, 39.
Turner, W.B. et al. (1983) Fungal Metabolites II, Academic Press, London.

Valparane and mulinane diterpenoids (VS6770, VS6780)

The valparanes and mulinanes are related to the fusicoccanes and are numbered
accordingly.

112
 19 19
20 15 20
18 18
9 14 9 14
8 10 8 10
13 13
7 11 12 7 11 12
6 1 6 1
5 17 2 15 5 17 2
4 3 4 3

16 16

Valparane Mulinane
Tetradecahydro-5a,8,10b-trimethyl-3-
(1-methylethyl)cyclohept[e]indene, 9CI

Spatane diterpenoids (VS6800, VS6810)

The spatane skeleton is formally derived from a prenylgermacrane by 1,5- and
6,10-cyclisation. The numbering system unfortunately does not reflect this
derivation. Spatanes and the related 4,10-secospatanes are marine natural
products.

12

3
10 4 5
2 6
9 8 7
1 19

13 16
11 18
14 15 17 20

Spatane
Decahydro-3a,6-dimethyl-1-(1,5-dimethylhexyl)cyclo-
buta[1,2:3,4]dicyclopentene, 9CI

Verticillane diterpenoids (VS6880)

The verticillane group is formally derivable from cembrane by an 11,15-
cyclisation. A non-cembrane numbering system is used. Only a few members of
this group have been reported.
18
6 7 8
4 5 17 9
19
3 15 20 10
2 16 12 11
1 14 13

Verticillane
4,8,12,15,15-Pentamethylbicyclo[9.3.1]pentadecane, 9CI

Taxane and 11(15→1)-Abeotaxane diterpenoids (VS6900, VS6950)

The taxanes form an important group of biologically active diterpenoids and
alkaloids from Taxus spp. The skeleton is related to verticillane by a further
cyclisation. The accepted numbering system is as shown. A large number of
11(15→1)-Abeotaxanes have been isolated recently.
18 18
19 19
10 9 10 9
12 11 7 12 7
16 8 6 11 8 6
13 15 13
17 5 14 1 3 5
14 1 3 4
2 2
4 15

20 16 17 20

Taxane 11(15→1)-Abeotaxane
Tetradecahydro-4,9,12a,13,13-pentamethyl-
6,10-methanobenzocyclodecene, 9CI

Appendino, G. (1995) Nat. Prod. Rep., 12, 349.

Das, B. (1996) Indian J. Chem., Sect. B., 35, 883.
Das, B. (1995) Planta Med., 61, 393.

113
Kingston, D.G.I et al. (1993) Prog. Chem. Org. Nat. Prod., 61, 1.
Swindell, C.S. (1993) in Studies in Natural Product Chemistry, Vol 12, (ed. Atta-ur-
Rahman), Elsevier, p. 170.

Trinervitane and kempane diterpenoids (VS7000, VS7010)

The trinervitanes, 7,16-secotrinervitanes, 17-methyltrinervitanes and kempanes
are constituents of the defence secretions of termites. Kempanes are 11,15-
cyclotrinervitanes. The numbering system of these unusual diterpenoids is as
shown.
19 19

8 9 8 9
6 7 17 10 6 7 17 10
5 20 5 11 20
4 11 4
16 16
15 12 15 12
18 3 1 13 18 3 1 13
2 14 2 14

Trinervitane Kempane
Hexadecahydro- Hexadecahydro-
1,4,8,12-tetramethyl- 2a,7,10,10c-tetramethyl-
1,11-ethanocyclopenta- napth-[2,1,8-cde]-
cycloundecane, 9CI azulene, 9CI

Amphilectane, cycloamphilectane, adociane and neoamphilectane

diterpenoids (VS7020, VS7030, VS7040)
The amphilectanes (including the pseudopterosins), the cycloamphilectanes and
adocianes (also called is isocycloamphilectanes) and neoamphilectanes are
marine products. They are found with serrulatane derivatives from which
amphilectanes are presumably derived by cyclisation. Cycloamphilectanes
represent a further cyclisation and adocianes have undergone a methyl
migration. Neoamphilectanes are 2(1 → 12) abeoamphilectanes

16 17
15
16
2 18 2 18
14 1
17 14
3 15 1 3
20 12 4 20 12 4
11 11
13 5 5
13
6 10 8 6
10 9 8 9
7 7

19 19

Amphilectane Cycloamphilectane
Dodecahydro-1,4,7-trimethyl- Hexadecahydro-1,4,7,7-
3-(2-methylpropyl)-1H- tetramethylpyrene
phenalene, 9CI

16 2 18 17
14 3
15 1 15
20 12 4 18
16 14
17 13 5
11 2 3
1
10 8 6 20 4
9 12 13
7 11 5
10 8 6
19 9 7

Adociane
19
Hexadecahydro-1,2,5,8-
tetramethylpyrene, 9CI Neoamphilectane

König, G.M. (1996) J. Org. Chem, 61, 3259.

114
Xenicane and xeniaphyllane diterpenoids (VS7100, VS7110, VS7150)
Xenicanes and xeniaphyllanes are marine natural products. Various nor-, seco-
and cyclo-xenicanes are listed in a separate section (VS7110). Xeniaphyllanes
are the diterpenoid equivalent of the caryophyllane skeleton. Xenicanes are
cleaved xeniaphyllanes.

16 17
14 15
15 13 14
16
12 13
11 12 20
4 20 2 3
5 4
10 6 18 11 1
17 3 5
7 10 9
2 6
8 8 7
18 1 9
19
19
Xeniaphyllane
Xenicane
2,6,10-Trimethyl-10-
1,2,6-Trimethyl-3-
(4-methylpentyl)-
(1,5-dimethylhexyl)-
bicyclo[7.2.0]undecane
cyclononane

Viscidane diterpenoids (VS7160)

Viscidanes, from Eremophila spp., are the diterpenoid equivalents of the
acoranes.
19

2 3
8 7
1 4 20
9 10
6 5

11 18
12
13 14

17
15
16

Viscidane
1,8-Dimethyl-4-(1,5-dimethylhexyl)spiro[4.5]decane

Eremane diterpenoids (VS7180)

Eremanes have an unusual carbon skeleton. They are isolated from Eremophila
spp.

14 13
17 15 8
20
16
18 9
10 7
6
19 1 5
11 2
3 4

12

Eremane
Decahydro-1,5,5-trimethyl-4-(4-methylpentyl)-
3a,6-ethano-3aH-indene

Prenyleudesmane, prenylgermacrane and prenylbicyclogermacrane

diterpenoids (VS7190, VS7200, VS7210)
These three groups of ‘extended’ sesquiterpenoid skeletons are largely of
marine origin.

115
 19

1 9
2 10 8
3 5 7 12 14 16
4 6 11 15
13

20 18 17

Prenyleudesmane
Decahydro-7-(1,5-methylhexyl)-1,4a-dimethylnaphthalene

1 9
2 10 8
3 5 19 7 12 14 16
4 6 11 15
13

20 18 17

Prenylgermacrane
4-(1,5-dimethylhexyl)-1,7-dimethylcyclodecane

5 4 3
6 2
7 9 18 1 16
8 10
13 15
11
19 12 14 17
20

Prenybicyclogermacrane
3,7,11-Trimethyl-11-(4-methylpentyl)bicyclo-
[8.1.0]undecane

Lobane diterpenoids (VS7220)

Lobanes are of marine origin and are ‘extended’ elemanes. A most unusual non-
standard numbering system is used in the literature.

7
8
6
9 1 5
11 2 4 15 17 20
10 3 13 18
16

12 14 19

Lobane
4-(1,5-dimethylhexyl)-1-ethyl-1-methyl-2-
(1-methylethyl)cyclohexane

Pachydictyane and cneorubin diterpenoids (VS7230, VS7240)

These two groups are also ‘extended’ sesquiterpenoids. The pachydictyanes are
prenylguaianes from marine organisms and the cneorubin group are
prenylaromadendranes found in leaves of Cneorum tricoccon.

18 14

10 9 10 9
2 2
1 1
8 3 8
3 5
4 5 4 7 19
6 7 16 6
11 12 13 14 15
11 16 18
17 15
12 17 20
19 20 13

Pachydictyane Cneorubin skeleton

Decahydro-7-(1,5-dimethyl- Decahydro-1,4,7-trimethyl-1-
hexyl)-1,4-dimethyl- (4-methylpentyl)-1H-
azulene cycloprop[e]azulene

Hardt, I.H. (1996), Phyhochemistry, 43, 71.

116
Serrulatane and biflorane diterpenoids (VS7250)
The biflorane skeleton is found in marine organisms, insects and Eremophila
spp. The skeleton is an ‘extended’ cadinane. The serrulatane name is given to
the aromatic analogue. Unfortunately different numbering systems have been
given to serrulatanes and bifloranes.
20 19

1 8 10 2
2 9 7 9 1 3
3 10 6 8 6 4
4 5 7 5
19 20
11 11
12 18 13 12
13 14
14 15
15
16
17 16 17 18

Serrulatane Biflorane
Decahydro-4-(1,5-dimethyl-
hexyl)-1,6-dimethyl-
naphthalene

Decipiane diterpenoids (VS7260)

Decipianes from Eremophila spp. are cyclised bifloranes. Yet another
numbering system is used for this skeleton.

20

11 13
10 12 14
9 17 15
8 16
7 19
6
18
5
4
2
3 1

Decipiane
Decahydro-1,2,5-trimethyl-1-(4-methylpentyl)-
1H-cyclobuta[de]naphthalene, 9CI

Sacculatane diterpenoids (VS7270)

Sacculatanes are ‘extended’ drimanes and are found in liverworts.

11
13
12
1 9
2 10 8
3 5 7
4 6

14 15

16
17

18
19 20

Sacculatane
Decahydro-1,4a,5,6-tetramethyl-1-(4-methylpentyl)-
naphthalene

Obtusane diterpenoids (VS7280)

The obtusanes, of marine origin, are bicyclic phytanes. The numbering system is
almost the same as for phytane. (Note that the terpenoid Obtusane itself is a
chamigrane).

117
 18 16
12 2
13 11 1 3
14 10 8 6 4
15 7 5
9
19 20 17

Obtusane
1,1,3-Trimethyl-2-[3-(4-methylcyclohexyl)butyl-
cyclohexane

Irieol diterpenoids (VS7290)

The irieol group, also of marine origin, represents an unusual diterpenoid
skeleton.
18

1
2 9 8
3 7
5 6
4

11 12 13
10
17 14
16 15

20
19

Irieol skeleton
Octahydro-1-[(3,3-dimethylcyclohexyl)methyl]-
3a,7-dimethyl-1H-indene

Sphenolobane diterpenoids (VS7300)

The sphenolobane skeleton is an ‘extended’ daucane skeleton.
14 15 17 20
18
13 16
2 1 10
9 19
11 3 8
6 7
4 5

12

Sphenolobane
Decahydro-1-(1,5-dimethylhexyl)-3a,6-dimethylazulene

Miscellaneous diterpenoids (VS7310–VS7340)

Diterpenoids that do not easily fit into the other categories are collected here.
Mono-, bi-, tri- and tetracyclic diterpenoids are listed separately in the Type of
Compound Index.

Sesterterpenoids (VS7400–VS7580)
Sesterterpenoids are a small group of natural products that arise from five
isoprene units. Although sesterterpenoids strictly have 25 carbons, there are
many nor- and alkylated members. Also included here are the C21 acyclic
terpenoids although their biosynthetic relationship with the sesterterpenoids has
not been established with certainty. Sesterterpenoids are found in fungi, higher
plants, insects and marine organisms.

Cordell, G.A. (1974) Phytochemistry, 13, 2343.

Crews, P. et al. (1985) Prog. Chem. Org. Nat. Prod., 48, 203.
González, A.G. et al. (1983) J. Nat. Prod., 46, 256.
Hanson, J.R. et al. (1996) Nat. Prod. Rep., 13, 529.
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 129.

118
Acyclic and noracyclic sesterterpenoids (VS7400)
The acyclic sesterterpenoids arise by a head to tail fusion of isoprene units. The
accepted numbering system is used here. The noracyclic sesterterpenoids
(VS7410) are numbered in a similar way; however, a problem arises with the
symmetry of the C21 compounds as they may be numbered from either end. The
acyclic sesterterpenoids frequently contain furanoid rings.
21 22 23 24 25

1
19 17 15 13 11 9 7 5 3
20 18 16 14 12 10 8 6 4 2

Acyclic sesterterpenoid skeleton

2,6,10,14,18-Pentamethyleicosane

C21 sesterterpenoid skeleton

3,7,11,15-Tetramethylheptadecane

Cyclohexane sesterterpenoids (VS7420)

Most of the cyclohexane sesterterpenoids arise by cyclisation of the acyclic
skeleton between carbons 14 and 19.
16 22
17 15
14 12 10 8 6 4 2
18 19 11 9 7 3
13 5 1

21 20 23 24 25

Cericerane sesterterpenoids (VS7440)

Cericeranes arise by cyclisation between carbons 1 and 14 of the acyclic
skeleton, retaining the numbering system. The symmetry of the cyclotetradecane
ring leads to some ambiguity of numbering (cf. cembranes).

24 25

7 8 9 11
6 23 10 12
5 1
4 2 14 13 21
3

17 19
15
22 16 18 20

Cericerane
1-(1,5-Dimethylhexyl)-4,8,12-trimethylcyclolotetradecane

Bicyclic sesterterpenoids (VS7460)

Various bicyclic sesterterpenoids are known. Some are prenylated analogues of
diterpene skeletons and the numbering systems are related to the corresponding
diterpenoid systems. Others have biogenetic numbering systems.

12 18
13 14 15 16 17
11 19
25 22
1 9 21 20
2 10 8
3 5 7
4 6

24 23

119
 24

24

12 14 16 18 13
12 11 23 22
25 11 13 17 10
15 19 14
22 16 9 1
15 17 8
1 9 7 5 3
21 20 6 4 2
2 10 8
3 5 7 25 18 20
4 6 19

23
24 21

23 16 18 25
15 17 19
21 8 9 10 24
7 14
13
11 12
6
5 2 1
4 3 22

20

Some bicyclic sesterterpenoid skeletons

Cheilanthane and ophiobolane sesterterpenoids (VS7500, VS7520)

The accepted numbering systems for the cheilanthanes and ophiobolanes are
shown here. Chemical Abstracts uses ophiobolane as a stereoparent; however it
uses a different numbering system for the non-ring carbons.
12 24
23 16 18 25
11 17 19
23 13
22 15
16
17 18 21 8 9
1 9 14 10
2 10 8 15 19 14 24
7
3 5 7 13
6 11 12
4 6 25
5 2 1

21 20 4 3 22

Cheilanthane 20
4,4,8-Trimethyl-D(15),24-
dinor-13,17-secocholane, 9CI Ophiobolane

16 17 19 21
15 20
18
25 8 9
7 10 14 22
13
6 11 12
5 2 1
4 3 23

24

Ophiobolane, CA numbering

Scalarane sesterterpenoids (VS7540)

The scalarane numbering system is shown here. Carbons 12, 24 and 25 are
generally oxygenated in this skeleton. Several methyl and dimethyl scalaranes
are found in marine organisms. The additional methyl groups attached to C-24
and C-20 are numbered 26 and 27 respectively.
25
23 24
12 18
11 13 17
22 21 14 16
1 9 15
2 10 8
3 5 7
4 6

20
19

Scalarane
4,4,8,17,17a-Pentamethyl-D-homoandrostane, 9CI

Bowden, B.F. (1992), J. Nat. Prod., 55, 1234.

120
Triterpenoids (VS7600–VS9450)
The triterpenoids constitute a large diverse group of natural products derived
from squalene or, in the case of 3β-hydroxytriterpenoids, the 3S-isomer of
squalene 2,3-epoxide. The conformation that all-trans-squalene 2,3-epoxide
adopts when the initial cyclisation takes place determines the stereochemistry of
the ring junctions in the triterpenoid produced. Thus cyclisation of the chair-
boat-chair-boat conformation gives the protostane cation and cyclisation of the
chair-chair-chair-boat conformation leads to the dammarane cation. The initially
formed cation intermediate may undergo a series of 1,2-hydride and methyl
migrations, commonly called backbone rearrangements, to give a variety of
skeletal types.

Squalene

O
Squalene 2,3-epoxide

HO

Protostane cation intermediate

Backbone rearrangement of the protostane cation gives the lanostane

skeleton; Lanosterol is the biogenetic precursor of the steroids in animals. The
methyl groups at carbons 4 and 14 are removed during steroid biosynthesis. The
steroid numbering system is adopted for lanostane and related tetracyclic
triterpenoids. The three methyl groups that were removed during the
biosynthesis of steroids are currently numbered 28, 29 and 30 as shown.
However, older literature uses the numbers 31, 30 and 32, respectively. This was
based on the assignment of carbon numbers 28 and 29 to the stigmastane ethyl
group, even though most lanostanes do not have such an ethyl group. The
numbering in DNP follows the currently accepted convention. (See also Steroid
section following). g

21 24 27
18 20
18
19 H 26
19 H
30

29 28

Lanostane numbering Steroid numbering

Abe, I. et al. (1993) Chem. Rev., 93, 2189.

Connolly, J.D. et al. (1972) in Chemistry of Terpenes and Terpenoids, (ed. A.A.
Newman) Academic Press, London, p. 207.

121
Connolly, J.D. et al. (1991) Methods Plant Biochem., 7, 331.
Connolly, J.D. et al. (1997) Nat. Prod. Rep., 14, 661.
Goodwin, T.W. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J.W. Porter et al.)
Wiley, New York, Vol. 1, p. 443.
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 131.
Mahato, S.B. et al. (1997) Phytochemistry, 44, 1185.
Spencer, T.A. (1994) Acc. Chem. Res., 27, 83.

The main tetracyclic triterpenoid skeletons have the steroid numbering for the
skeleton including the side chain and only the methyl groups will be numbered
in the structures that follow. As a general rule the methyls which migrate during
terpenoid biosynthesis retain their numbering.
CA names most tetracyclic triterpenoids as derivatives of the steroid
stereoparents. This has the disadvantage that some are assigned different names
from those commonly used. The CA names for some common skeletons are
listed below.

Chemical Abstracts name

Protostane Dammarane, (8α, 9β, 13α, 14β)-
Fusidane 29-Nordammarane, (4α, 8α, 13α, 14β)-
Cycloartane 9,19-Cyclolanostane
Cucurbitane 19-Norlanostane, 9-methyl-, (9β, 10α)-
Euphane Lanostane, (13α, 14β, 17α)-
Tirucallane Lanostane, (13α, 14β, 17α, 20S)-
Apotirucallane Cholestane, 4,4,8-trimethyl-,
(13α, 17α, 20S)

The CA nomenclature of some other triterpenoids is idiosyncratic, e.g.

Malabaricanes.

Linear triterpenoids (VS7600)

This group contains simple derivatives of squalene. The preferred numbering
system is shown and is used for the related polyether derivatives found in
marine algae, e.g. Laurencia spp. Also included are C30 polyprenols, and some
homo- and nor-squalenes. Squalene is formed biosynthetically from farnesyl
pyrophosphate via presqualene pyrophosphate.

25 26 27

24
1 10

28 29 30

Squalane
2,6,10,15,19,23-Hexamethyltetracosane, 9CI

O O H
HO P O P OH2C
OH OH
Presqualene pyrophosphate

Julia, M.Y. (1991) Chem. Soc. Rev., 20, 129.

Poulter, C.D. et al. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J.W. Porter et
al.) Vol. 1, Wiley, New York, p. 413.

122
Botryococcene triterpenoids (VS7620)
The alga Botryococcus braunii produces a series of branched alkylated
isoprenoid hydrocarbons based on botryococcane. The names of individual
compounds indicate the number of carbons, e.g. C34-Botryococcene. Of the
several numbering systems that have been used, the one below is preferred.
Cyclised botryococcenes are also listed in this section.

27
23 24 26
22
1 3
25
28 29 30

C30-Botryococcane
10-Ethyl-2,6.10,13,17,21-hexamethyldocosane

Prostostane and fusidane triterpenoids (VS7700)

The protostanes, e.g. Protosterol, form a small group that arise from cyclisation
of squalene or its 2,3-epoxide without backbone rearrangement. The fusidanes
form a small but important group of antibiotics, e.g. Fusidic acid, which lack
one of the methyl groups at carbon 4. The numbering and stereochemistry of
these skeletons is indicated below.

H H

19 30 30
19

H 18 18
H

29 28 28
Protostane Fusidane

Lanostane triterpenoids (VS7750)

Backbone rearrangement of the protostane cation leads to the lanostanes, a large
group. Lanosterol is a key intermediate in steroid biosynthesis. They are
uncommon in plants but some fungi, e.g. Ganoderma lucidum, are a prolific
source. Some rearranged lanostanes are also included in this section.

18

19 H
30

29 28
Lanostane

The nomenclature of the numerous G. lucidum products is highly confused

owing to the application of identical trivial names to compounds of different
structure by several different groups working simultaneously (for full details,
see individual entries). It is recommended that systematic nomenclature be used.

Cycloartane triterpenoids (VS7800)

Backbone rearrangement of the protostane cation including cyclisation to form a
9,19 bond produces the cycloartane skeleton. Plants use Cycloartenol and not
Lanosterol for the biosynthesis of phytosterols. Cycloartanes are often named as
9,19-Cyclolanostanes in the literature.

123
 18

19
H
30

29 28
Cycloartane

Cucurbitane triterpenoids (VS7900)

More extensive backbone rearrangement of the protostane cation affords the
cucurbitane skeleton. The cucurbitacins, e.g. Cucurbitacin A, are found in the
Cucurbitaceae and are of interest because of their biological activity. Many
occur as glycosides.

18

H H
19 30

29 28
Cucurbitane

Lavie, D. et al. (1971) Prog. Chem. Org. Nat. Prod., 29, 307.
Miro, M (1995), Phytother. Res., 9, 159.

Dammarane triterpenoids (VS7950)

Collapse of the dammarane cation without backbone rearrangement leads to the
dammarane skeleton (a stereoisomer of protostane). Dammaranes often occur as
glycosides and are commonly found among the much-studied saponins of
ginseng.

H
H
19 30

18

29 28
Dammarane

Tanaka, O. et al. (1984) Prog. Chem. Org. Nat. Prod., 46, 1.

Tirucallane/euphane triterpenoids (VS8000)

Backbone rearrangement of the dammarane cation (analogous to the protostane-
lanostane rearrangement) yields the euphane skeleton and its 20-epimer, the
tirucallane skeleton. There is frequent confusion in the literature about the
stereochemistry at carbon-20 in these compounds.
20 20
18 18
H H
19 H 19 H
30 30

29 29 28
28
Euphane Tirucallane

124
Apotirucallane triterpenoids (VS8050)
Further rearrangement of the tirucallane skeleton, the apo-rearrangement,
affords the apotirucallane skeleton. Apotirucallanes are the notional parents of
the tetranortriterpenoids (limonoids) and the quassinoids.

18

19 30

29 28
Apotirucallane

Nortriterpenoids (VS8100–VS8130)
The tetranotriterpenoids (limonoids) are formed by loss of four terminal carbons
of the apotirucallane skeleton. The side chain is typically a β-substituted furan
although other oxidation levels are found to a lesser extent. A series of ring-
cleavages and rearrangements can lead to a wide range of structures. For
example cleavage of rings B and C may be followed by cyclisation to form a
bicyclo[3.3.1]nonanolide system. In the Type of Compound Index, these com-
pounds are presented in three groups – intact tetranortriterpenoids (VS8100),
ring cleaved derivatives (VS8120) and rearranged derivatives (VS8130). The
last group contains the bitter principles of the Cneoraceae, e.g. Cneorin C.

O O

18

O
19 30
8
O
O
30
O
29 28
COOMe
Tetranortriterpenoid A tetranortriterpenoid with
skeleton rings B and D cleaved

18

7
O
MeOOC 9
8
O O
5
30
3

O
A bicyclo[3.3.1]nonanolide tetranortriterpenoid

Isman, M.B. et al. (1996), Recent Adv. Phytochem., 30, 155.

Mondon, A. et al. (1983) Prog. Chem. Org. Nat. Prod., 44, 101.
Taylor, D.A.H. (1984) Prog. Chem. Org. Nat. Prod., 45, 1.

Quassinoid nortriterpenoids (VS8200, VS8205)

The quassinoids are found in the Simaroubaceae family and are closely related
to the tetranortriterpenoids. This relationship is emphasised by the presence of
several C25 precursors (e.g. Simarolide) which lose a further five carbon atoms
to give the C20 picrasane skeleton. C18 and C19 quassinoids are also known but
are less common. The quassinoids have attracted much synthetic effort because
of their cytotoxic activity. Chemical Abstracts uses the picrasane skeleton as a

125
stereoparent; however the numbering system used by Chemical Abstracts differs
from the accepted system; the oxygen atom is numbered.
18 22 18
12 17 12
11 13 20 23 11 13
19 30 14 19 3014
1 9 21 1 9
2 10 8 15 2 10 8 15
3 5 3 5 7
H 16
7
4 6 16 4 6
O
28 28

C25 Quassinoid Picrasane (C20)-

skeleton usual numbering

21
12
11 13
19 2014
1 9
2 10 8 15
3 5 7 17 16
4 6
O
18

Picrasane, CA numbering

Kawada, K. et al. (1989) Org. Prep. Proced. Int., 21, 521 (synth).
Polonsky, J. (1973) Prog. Chem. Org. Nat. Prod., 30, 101; (1985) 47, 221.

Baccharane triterpenoids (VS8230)

Cyclisation of squalene or squalene 2,3-epoxide in the chair-chair-chair-boat
conformation leads initially to the baccharane skeleton. Backbone
rearrangement of this skeleton leads to the lemnaphyllane and shionane
skeletons (listed in the miscellaneous triterpenoid group). Chemical Abstracts
treats this group as 18,19-secolupanes. The numbering system parallels that of
lupane apart from the carbon atoms of ring D. Occasionally a steroid-like
numbering system is used. This cyclisation of squalene provides an entry into
the pentacyclic triterpenoids.
30

H 28 20 22
12 18
11 13 17 19 21 29
25 26 14 16
1 9 15
2 10 8
27
3 5 7
4 6

24 23

Baccharane
D : B-Friedo-18,19-secolupane, 9CI

Lupane triterpenoids (VS8250)

Formation of a five membered ring E from the baccharane precursor affords the
lupane skeleton whose numbering system is as shown. 3(2 → 1)-Abeolupanes
(VS8260) and assorted nor-, friedo- and seco-lupanes (VS8270) are listed
separately.
29

20
30 21
19
H 22
12 18
11 13 17 28
25 26 14 16
1 9 15
2 10 8
27
3 5 7
4 6

24 23

Lupane, 9CI
(23/24 substituents specified in CA as (4α)23- and
(4β)23- respectively)

126
Oleanane triterpenoids (VS8300)
Formation of a six-membered ring E from the baccharane precursor leads to the
oleanane group. Oleananes form the largest group of triterpenoids and occur
widely in the plant kingdom often as glycosides. The fairly numerous nor-,
seco- and abeooleananes are listed separately (VS8310).

30 29

20
19 21
18 22
12
11 13 17 28
25 26 14 H 16
1 9 15
2 10 8
27
3 5 7
4 6

24 23

Oleanane, 9CI
(23/24 substituents specified in CA as (4α)23- and
(4β)23- respectively; and 29/30 substituents as (20α)29
and (20β)29 respectively)

Agrawal, P.K. et al., (1992), Prog. Nuclear Magn. Reson. Spect., 24, 1.
Mahato, S.B. et al. (1988) Phytochemistry, 27, 3037.
Tschesche, R. et al. (1973) Prog. Chem. Org. Nat. Prod., 30, 461.

Taraxerane, multiflorane, glutinane and friedelane triterpenoids

(VS8350–VS8510)
These triterpenoids arise by increasing degrees of backbone rearrangement of
the oleanane skeleton.
30 29 30 29

27 27

H 28 H 28
25 26 25

26

24 23 24 23

Taraxerane Multiflorane
D -Friedooleanane, 9CI D : C-Friedooleanane, 9CI

30 29 30 29

27 27

H 28 H 28

25 26 25 26

24
24 23 23

Glutinane Friedelane
D : B-Friedooleanane, 9CI D : A-Friedooleanane, 9CI

Chandler, R.F. et al. (1979) Phytochemistry, 18, 711.

Gunatikala, A.A.L. (1996), Prog. Chem. Org. Nat. Prod., 67, 1.

Pachysanane triterpenoids (VS8520)

The pachysananes are friedelane derivatives which have the C-28 methyl group
attached to C-16.

127
 30 29

27

H
28
25 26

24
23

Pachysanane
16-Methyl-D : A-friedo-28-noroleanane, 9CI

Taraxastane, ursane and bauerane triterpenoids (VS8550–VS8700)

Methyl migration in ring E of the oleanane precursor leads to the taraxastane
skeleton (following proton loss) or to the stereoisomeric ursane skeleton
(following a series of hydride shifts). These two systems are often confused in
the literature. The bauerane skeleton is related to ursane by backbone
rearrangement.
30 30

29 29

H 28 H 28
25 26 25 26

27 27

24 23 24 23

Taraxastane Ursane, 9CI

30

29
27

25 H 28

26

24 23

Bauerane
D : C-Friedoursane, 9CI

Hopane triterpenoids (VS8720, VS8730)

Cyclisation of squalene in the chair-chair-chair-chair-chair conformation affords
the hopane skeleton and following a ring E expansion step, the gammacerane
skeleton (see below). Degraded and extended hopanes occur widely in natural
sediments. 21αH-Hopanes (moretanes) arise by cyclisation of squalene in the
chair-chair-chair-chair-boat conformation.

29
H H 21

28
25 26 30

27

24 23

Hopane
A′-Neogammacerane, 9CI

Ourisson, G. et al. (1992) Acc. Chem. Res., 25, 403.

128
Neohopane, fernane, adianane and filicane triterpenoids (VS8770,
VS8800, VS8850, VS8870)
Backbone rearrangement of the moretane skeleton leads in turn to the
neohopanes (neomotianes), fernanes, adiananes and filicanes.
29 29
28 26 28

25 26 H 30 25 H 30

27 27

24 23 24 23

Neohopane Fernane
B′ : A′-Neogammacerane, 9CI D : C-Friedo-B′ : A′-
neogammacerane, 9CI

29 29
27 28 27 28
22 22

H 30 H 30

25 26 25 26

24
24 23 23

Adianane Filicane
D : B-Friedo-B′ : A′- D : A-Friedo-B′ : A′-
neogammacerane, 9CI neogammacerane, 9CI

Murakami, T. et al. (1988) Prog. Chem. Org. Nat. Prod., 54, 1.

Arborinane and stictane triterpenoids (VS8850, VS8900)

Cyclisation of squalene, or its 2,3-epoxide, in the chair-boat-chair-chair-boat
conformation followed by ring expansion of ring E yields the stictane skeleton.
Members of this group occur in lichens, e.g. Sticta spp. Backbone
rearrangement of this initial cyclisation product gives the arborinane skeleton.
Two variants to this series Boehmerol and Boehemerone have undergone
partial backbone rearrangement. (See under Miscellaneous triterpenoids).
30
29 29
27 28 22

28
25 H 30 25 26

26 H 27

24 23 24 23

Aborinane Stictane
D : C-Friedo-B′ : A′- 21,21-Dimethyl-29,30-
neogammacerane, 9CI dinorgammacerane, 9CI

Gammacerane triterpenoids (VS8950)

The gammacerane skeleton arises from the same cyclisation as hopane. The
most notable gammacerane derivative is Tetrahymenol, a metabolite of the
protozoon Tetrahymena pyriformis, whose hydroxyl function is derived from
water and not from squalene oxide.

129
 H H 30
28 29
25 26

27

24 23

Gammacerane, 9CI

Serratane and onocerane triterpenoids (VS9000, VS9050)

Cyclisation of squalene, or more likely, its bisepoxide, from both ends affords
the onocerane skeleton. Further cyclisation leads to the serratane skeleton.

H H 30
H H 30

28 29 28 29
25 26 25 27

26
27

24 23 24 23

Serratane Onocerane
C(14a)-Homo-27- 8,4-Secogammacerane, 9CI
norgammacerane, 9CI

Polypodane, malabaricane and podiodane triterpenoids (VS9080,

VS9100)
Partial cyclisation of squalene 2,3-epoxide from one end leads to the
polypodane and the malabaricane groups. The podiodanes are malabaricanes
which have undergone a methyl migration. The isomalabaricane skeleton (8,9-
diepimer of malabaricane) has recently emerged. The most widely used
numbering systems are given below.
27 28 29

12 16 20
11 14 18 22
13 15 17 19 21 30
25
1 9 26
2 10 8
3 5 7
4 6

24 23
Polypodane

11 12
19 30 13 15 17 22 24 26
1 9 14 16 20 23 25
2 10 8
H
3 5 7
4 6 18 21 27

29 28
Malabaricane
15-Methyl-D-homo-C,30-dinor-13,17a-secodammarane, 9CI

26
25 24

27 28 30

24 23
Podiodane

Miscellaneous triterpenoids (VS9300)

This group contains assorted triterpenoid skeletons which are less easily
classified. It includes intriguing compounds such as Sipholenone C from the
sponge Siphochalina siphonella.

130
Iridal group norterpenoids (VS9350)
The iridals are constituents of Iris spp. which serve as the precursors of the
important perfumery chemicals, the irones. The numbering system of iridal is
based on that of squalene. The irones are also included in this section. The
numbering system of the irone skeleton is based on the carotenoids.
28 29 30

13 15 17 21 23
12 20
19 24
26 14 16 18 22
3 5 27
HOH2C 4 11
6 10 OH
2 7 9
OHC 8
1

25

Iridal

13 12
O
7 9
14 1
2 6 8 10
3 5
4
15

Irone

Jaenicke, L. et al. (1986) Prog. Chem. Org. Nat. Prod., 50, 1.

Jaenicke, L. et al. (1990) Pure Appl. Chem., 62, 1365.

Tetraterpenoids (VS9400)
The tetraterpenes arise by head to head coupling of two
geranylgeranylpyrophosphate molecules.

Spurgeon, S.L. et al. (1981) in Biosynthesis of Isoprenoid Compounds, (eds J.W. Porter
et al.), Wiley, New York, Vol. 2, p. 1.

Carotenoids
These include the hydrocarbons (carotenes) and their oxygenated derivatives
(xanthophylls). Carotenoid nomenclature is based on a stem name, carotene, and
two Greek letters as prefixes to define the two end groups. The numbering
system and end groups are given below.

131
 17 18 19 20

1 3 5 7 15 14′ 12′ 10′ 8′ 6′ 4′ 2′ 16′

2 4
16 9 11 13
6 8 10 12 14 15′ 11′ 7′ 3′

20′ 19′ 18′ 17′

ψ,ψ-Carotene

16 17 16 17 16 17
17 18
1 1 1
3 2 6 2 6 2 6
1 5
2 3 5 3 5 3 4 5
16 4 6 4 4
18 18 18

ψ β γ ε

16 16
17 6
16
17 17
1 1 6 1 6
5 18 2 2
2 3 3
3
4 4 5 4 5
18 18

κ φ χ

Carotenoid end-groups

IUPAC treats ‘hydro’ prefixes in carotenoid names as non-detachable. This

Dictionary follows IUPAC recommendations for nomenclature except that the
‘hydro’ prefix is treated as detachable and is placed alphabetically with the other
prefixes. CA also uses a detachable ‘hydro’ prefix but it does not use
hypothetical parents such as β-caroten-6-ols which are incapable of existence
(see current Chemical Abstracts Index Guide). The following examples illustrate
this point.

IUPAC name Chemical Abstracts name

5,6-Dihydro-β,β-caroten-3-ol 5,6-Dihydro-β,β-caroten-3-ol
5,6-Dihydro-β,β-caroten-6-ol 5,6-Dihydro-6-hydroxy-β,β-carotene

Britton, G. (1991) Methods Plant Biochem., 7, 473.

Britton, G. (1991) Nat. Prod. Rep., 8, 223.
Goodwin, T.W. (1980) Biochemistry of the Carotenoids, 2nd edn. Chapman & Hall,
London.
Goodwin, T.W. (1992) Methods Enzymol., 213, 167.
Hill, R.A. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson),
Blackie, Glasgow, pp. 135.
IUPAC (1975) Pure Appl. Chem., 41, 407.
Pfander, H. (1981) Key to Carotenoids, Birkhäuser, Basel.
Pfander, H. (1992) Methods Enzymol., 213, 3.
Ramage, R. (1972) in Chemistry of Terpenes and Terpenoids, (ed. A.A. Newman),
Academic Press, London, p. 288.
Sandmann, G. (1994) Eur. J. Biochem., 223, 7.

132
Miscellaneous terpenoids (VS9450–VS9910)
Megastigmane norterpenoids (VS9450)
This is a fairly large group of C13 compounds generally thought to be degraded
carotenoids or catabolites of abscisic acid.
11 12
7 9
1
2 6 8 10
3 5
4
13

Megastigmane
2-Butyl-1,1,3-trimethylcyclohexane

Izoe, S. et al. (1969) Tetrahedron Lett., 279.

Powell, R.G. et al. (1986) J. Org. Chem., 51, 1074.

Apocarotenoids (VS9700)
Apocarotenoids are carotenoids in which the carbon skeleton has been shortened
by the formal removal of fragments from one or both ends. A locant is used to
indicate that all the molecule beyond the carbon with that locant has been
removed. It is not necessary to give a Greek-letter end group designation if the
apo-locant is greater than 5.

Polyterpenoids (VS9800)
This section includes the higher carotenoids and polyprenols with more than 40
carbons.

Britton, G. (1991) Nat. Prod. Rep., 8, 223.

Tanaka, Y. (1991) Methods Plant Biochem., 7, 519.

Meroterpenoids (VS9900)
Meroterpenoids are of mixed biogenesis containing terpenoid and non-terpenoid
derived fragments. This broad definition could include the vast number of
simple prenylated phenolics but is normally reserved for compounds where the
terpenoid fragment comprises a large part of the molecule. The polyprenylated
quinones and chromanols typified by the ubiquinones and tocopherols are
clearly of mixed biogenesis but the metabolites of Aspergillus ustus such as
Austin could be mistaken for sesterterpenoids. In fact these metabolites have
been shown to be derived from a sesquiterpenoid fragment and an aromatic
polyketide fragment.

O
MeO CH3
MeO
H
O 10

Ubiquinone 10

CH3
HO
H3C
CH3 O

α-Tocopherol

133
 O O
AcO
OH

O
O
O O
Austin

Ahmed, S.A. et al. (1989) J. Chem. Soc. Perkin Trans 1, 807.

Hubscher, M. et al. (1990) Helv. Chim Acta, 73, 782; 1068.
Konishi, K. et al. (1987) Chem. Pharm. Bull., 35, 1531.

Hop meroterpenoids (VS9910)

The bitter hop constituents exemplified by Adhumulone and the ring contracted
Hulupone have been shown to be derived by prenylation of a polyketide
aromatic ring.

O
OH
O O

O O
OH
OH
O

Hulupone
Adhumulone

Drawert, F. et al. (1976) Phytochemistry, 15, 1689; 1695.

134
Steroids (VT)
For general information on the biogenesis of steroids, see the preceding
terpenoid section.
The steroid structure is based on four carbocyclic rings arranged as in
cyclopenta[a]phenanthrene, which is normally fully or partially reduced so that
only limited unsaturation, if any, is present. The four steroid rings are labelled,
and their carbon atoms are numbered according to the universal convention
illustrated.
12 17
11 13
C 14 D 16
15
1 9
2 10 8
A B
3 5 7
4 6

Cyclopenta[a]phenanthrene Basic steroid structure

The great majority of steroids also have one or two methyl groups present at
the bridgehead positions C-10 and C-13; the methyl carbon atoms are numbered
C-19 and C-18, respectively.
18

19

Methyl groups, hydrogen atoms, or substituents at the bridgehead positions

C-8,9,10,13, and 14 are assumed to have the 8β, 9α, 10β, 13β, 14α
configurations unless otherwise specified. C-5 is a special case, as there are
many steroids of each of the 5α and 5β configurations, and it is therefore
necessary to specify the C-5 configuration for any steroid which is saturated at
C-5. (e.g. 5α-Androstane or 5β-Androstane).
It is worth noting here some changes in Chemical Abstracts indexing policy.
Prior to the 8th Collective Index (1967), the indexing of steroid stereoisomers
gave priority to the C-5 configuration which effectively led to a separation of
5α- and 5β-steroids. Users should be alert to this when searching the literature
before 1967.

H H

H
5α-Androstane

The hydrogen atoms at C-8,9, and 14 are generally omitted from formulae if
they have the natural configurations shown here.
Any side-chain at C-17 is assumed to have the 17β-configuration unless
otherwise indicated. This is shown either by using a wedge bond or, where there
is any possibility of uncertainty owing to substitution at C-20, by drawing in the
C-17 α-hydrogen atom.
Configurations of substituents in the side chain were formerly also indicated
by α or β, according to a convention devised by Fieser, whereby the side-chain
is drawn in Fischer projection, with the highest numbered locant at the top.

135
 H OH HO H

20α-form 20β-form
The Fieser convention for pregnan-20-ols

However, use of this arbitrary system demands either a good memory or

reference to printed texts. The unambiguous Cahn-Ingold-Prelog sequence rule
descriptors (R or S) are now recommended for side-chain configurations.
Designations according to Fieser’s system are also given in DNP entries where
these are or have been in widespread use.

OH H
H OH
H H

20S (≡ 20α) 20R (≡ 20β)

The presence of substituents at C-17 or C-21 may change the priority of

groups so that 20S is no longer equivalent to 20α. This happens for example in
the pregnane-20,21-diols.
H OH
HOH2C OH HOH2C H
H H

20S (≡ 20β) 20R (≡ 20α)

Difficulty in labelling configurations unambiguously can also occur in

secosteroids, in which a ring bond has been broken. Parts of the molecule which
are normally constrained when the rings are intact become free to rotate in
relation to each other so that α and β lose their defined meanings. The sequence
rule is again recommended to overcome this problem. The compounds of the
Vitamin D series (9,10-secosteroids) are the most important in this class.
The sequence rule descriptors (E-) and (Z-) are required for defining side-
chain double bond configurations.

H H

(E)-5α-Pregn-17(20)-ene (Z)-5α-Pregn-17(20)-ene
5α-Pregn-17(20)E-ene 5α-Pregan-17(20)Z-ene

(Note that both locants for unsaturation are required when

the numbers are non-consecutive.)

Bernstein, S. et al. (1968) Physical Properties of Steroid Conjugates, Springer-Verlag,

Berlin.
Danielsson, H. and Sjövall, J. (1985) Sterols and Bile Acids, Elsevier, Amsterdam.

136
Duax, W.L. and Norton, D.A. (eds) (1975) Atlas of Steroid Structure, Vol. 1; Vol. 2
(1984) Plenum, New York.
Fieser, L.F. and Fieser, M. (1959) Steroids, Reinhold, New York.
Goad, L.F. and Akihisa, T. (1997) Analysis of Sterols, Blackie, London.
Hanson, J.R. (1997) Nat. Prod. Rep., 14, 373.
Hill, R.A., Kirk, D.N., Makin, H.L.J. and Murphy, G.M. (1991) Dictionary of Steroids,
Chapman & Hall, London.
Makin, H.L.J. (ed.) (1984) Biochemistry of Steroid Hormones, 2nd edn, Blackwell,
Oxford
Nair, P.P. and Kritchevsky, D. (eds) (1971) The Bile Acids, Vol. 1; Vol. 2 (1973); Vol. 3
(1976); Setchell, K.D.R., Kritchevsky, D. and Nair, P.P. (eds) (1988) Vol. 4,
Plenum, New York.
Turner, A.B. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H.
Thomson), Blackie, Glasgow, pp. 140.
Zeelen, F.J. (1990) Medicinal Chemistry of Steroids, Elsevier, Amsterdam.
Zeelen, F.J. (1994) Nat. Prod. Rep., 11, 607 (synth).

In the notes which follow, the carbon numbers used to classify the different
types of steroids refer only to those which constitute the parent steroid skeleton.
They do not include any carbon atoms which may be present as substituents
(e.g. 6-methyl), or in derivative groups such as the ethers or esters of steroid
alcohols. Within the Type of Compound Index, the steroid groups are arranged
in order of increasing carbon number, which may not correspond exactly with
the order in which they are discussed in the following sections.

Estrane steroids (aromatic ring A, C18) (VT0100)

Estrane (oestrane) is the parent hydrocarbon of the estrogens, the hormones
responsible for development of the female reproductive organs and secondary
sex characteristics. The original spellings ‘oestrogen’ and ‘oestrane’, although
still used, are superseded by the form with the initial ‘o’ omitted.
The estrogens have an aromatic ring A. Two ‘Kekulé’ forms can be drawn, as
for all benzene derivatives.
O O
17
1
10
2

3
5
4

(i) [1,3,5(10)-triene] (ii) [1(10),2,4-triene]

Kekulé forms of Estrone

For purposes of naming and illustrating estrogens the form (i) is preferred;
the natural estrogens are accordingly derivatives of estra-1,3,5(10)-triene. They
have a hydroxyl group at C-3, and hydroxyl or carbonyl at C-17. Some
metabolites have additional oxygen functions elsewhere.
The trivial names and abbreviations of Estrone (3-hydroxyestra-1,3,5(10)-
trien-17-one), Estradiol (estra-1,3,5(10)-triene-3,17β-diol) and Estriol (estra-
1,3,5(10)-triene-3,16α,17β-triol), are commonly used, especially in biochemical
and medical contexts. These trivial names are sometimes incorporated into those
of derivatives (e.g. 17α-Methylestradiol).
Equine estrogens, with unsaturation additionally in ring B, belong to the
estra-1,3,5(10),7-tetraene and estra-1,3,5,7,9-pentaene series. Note the
recommended change in numbering for unsaturation in the latter case, where it
is possible to avoid the need for a compound locant [5(10)].

137
 O

H
HO

3-Hydroxyestra-1,3,5,7,9-pentaen-17-one

Androstane steroids (C19) (VT0250)

Androstane is the parent hydrocarbon of the male hormone Testosterone (17β-
hydroxyandrost-4-en-3-one) and its derivatives and metabolites. The androstane
ring structure with the two bridgehead methyl groups is common to most other
groups of steroids (pregnanes, cholanes, cholestanes, etc) which have side-
chains at C-17 and are discussed individually below.

OH

17β-Hydroxyandrost-4-en-3-one (Testosterone)

Zhou, Z.X. et al. (1994) Recent. Prog. Hormone Res., 49, 249.

C20 steroids (VT0400)

These are scarce among natural products, and are limited to a few 19-nor-
pregnanes, with the pregnane skeleton (see below) but lacking the bridgehead
methyl group (C-19). Alternative names based upon 17-ethylestrane are also
often used for this series of compounds (see pregnanes).

19-Norpregnane

Pregnane steroids (C21) (VT0450)

Pregnane is the parent hydrocarbon of the pregnancy hormone progesterone
(pregn-4-ene-3,20-dione), and of the great majority of the corticosteroids and
many other natural products, which together make the pregnanes the largest
single group of steroids. The skeletal structure comprises androstane with a two-
carbon (ethyl) chain at C-17. The chain is in the β-configuration unless 17α-
pregnane is specified.
21
20 O
17

O
Pregn-4-ene-3,20-dione (Progesterone)

Many pregnane derivatives have hydroxyl or a related group at C-17. To

avoid any ambiguity as to the configuration, epimeric forms of 17-substituted
pregnanes are specified in DNP as 17αOH or 17βOH.

138
Norcholan-23-oic acid (C23) and cholan-24-oic acid (C24) steroids
(VT0650, VT0800)
The largest single group in this class comprises the bile acids, the majority of
which are cholan-24-oic acids. The shorter form ‘cholanic acid’ has been widely
used but is not recommended.
Naturally occurring bile acids are mainly 5β-cholan-24-oic acids with
hydroxyl substitution at C-3, and variously at other sites. The orientation of the
hydroxyl groups is usually α-, and bile acids have well-defined polar and non-
polar regions. This amphipathic quality of bile acids is essential to their
physiological functions.
Bile acids are biosynthesised from cholesterol; primary bile acids directly so
(e.g. Cholic acid, Chenodeoxycholic acid); subsequent action by intestinal
bacteria yields secondary bile acids (e.g. Deoxycholic acid, Lithocholic acid).

COOH

HO
H
3α-Hydroxy-5β-cholan-24-oic acid (Lithocholic acid)

Omission of one of the side chain carbon atoms leads to the 24-nor series
(24-norcholan-23-oic acids); loss of two carbon atoms gives the 23,24-
dinorcholan-22-oic acids. The latter are sometimes named as pregnane-20-
carboxylic acids, requiring a sequence-rule descriptor of the C-20 configuration.

H
COOH
H

H
23,24-Dinor-5α-cholan-22-oic acid
5α-Pregnane-20S-carboxylic acid

Whenever cholane nomenclature is used, the side chain has the C-20
configuration which is illustrated above for Lithocholic acid (20R, in the
absence of substituents at or near C-20), unless the opposite is specified.

Haslewood, G.A.D. (1978) The Biological Importance of Bile Salts, North-Holland,

Amsterdam.

Cardanolide steroids (C23) (VT0750)

Cardanolide is the parent compound of the Digitalis glycosides and comprises
the androstane skeleton with a γ-lactone ring attached at C-17. The
configuration at C-5 must be stated, but is frequently β. Prior to the most recent
IUPAC-IUB recommendations (1989), the 14α-configuration was assumed
unless the 14β-configuration was indicated as an affix. Almost all natural
products in these series, however, are of 14β type, and the convention for C-14
has been reversed so that the cardanolide name implies 14β-configuration. This
is in contrast to the rule for all other steroid classes. The change from the older
system, which has been in use for several decades, seems likely to lead to
confusion and so the C-14 configuration is specified for all such compounds in

139
DNP. The formulae illustrated below also show the 17β and 20R configurations
which are implied in the absence of a contrary indication.
The naturally occurring compounds generally have a 20(22)-double bond and
are commonly called cardenolides, for example Digitoxigenin is 3β,14β-
dihydroxy-5β-card-20(22)-enolide. The cardenolide glycosides are of particular
interest because of their cardiac activity.

O O O O
23
21 H
22

H
H H
OH
HO
H H
5β-Cardanolide Digitoxigenin

Connolly, J.D. et al. (1991) Methods Plant Biochem., 7, 369.

Deepak, D. (1996), Prog. Chem. Org. Nat. Prod., 69, 71.
May, P.M. (1990) Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, Vol. 2,
p. 206.

Bufanolide steroids (C24) (VT0900)

Bufanolide also has the androstane skeleton but in this case a δ-lactone ring is
attached at C-17. It is the parent compound of the cardioactive constituents
obtained from toad skin secretions and the sea onion or squill (Scilla maritima).
As for the cardanolides, 14β-, 17β- and 20R-configurations are implied in the
name. The naturally occurring compounds are generally doubly unsaturated in
the lactone ring (bufa-20, 22-dienolide), and often occur as glycosides or as
conjugates.
O

H
H

H
5β-Bufa-20,22-dienolide

The sterols
The sterols comprise several major groups of steroids characterised by having a
hydroxyl group at C-3, normally in the β-configuration, and branching side
chains of from eight to ten or more carbon atoms at C-17. They occur widely
throughout the animal and particularly the plant kingdoms. They have both
structural roles, as membrane constituents, and a key place in the biosynthetic
sequences which lead to the steroid hormones and other biologically active
steroidal species.
The following sections detail the main features of the various parent
hydrocarbons which provide the structural basis and classification of the sterols.

Good, L.J. (1991) Methods Plant Biochem., 7, 369.

Kerr, R.G. et al. (1991) Nat. Prod. Rep., 8, 465.
Minale, L., (1993), Prog. Chem. Org. Nat. Prod., 62, 75.

140
Cholestane steroids (C27) (VT1050, VT1100)
The cholestane skeleton, which derives its name from the longest-known and
most familiar compound of its class, Cholesterol, can be regarded as the parent
from which almost all other sterols are derived. This is true structurally, if not
necessarily in terms of the detailed biosynthetic pathway.
H 22 24 26
21
20 23 25

17
H 27
H

H
Cholestane (5α- or 5β-Cholestanes)

Other classes of sterols are derived from cholestane by the addition of one or
more carbon atoms at side-chain positions, most commonly C-24 (see
ergostanes, stigmastanes, etc, below).
Several other steroid classes have structures based upon the C27 cholestane
framework, although this is not always immediately apparent from the formulae
as drawn. The ecdysteroids (insect moulting hormones) are highly oxygenated
cholestanes. Many plant products that are commonly classified as tetracyclic
triterpenes are cholestanes with altered stereochemistry and/or additional methyl
substitution in the ring system, notably at C-4, -8, or-14. The dividing line
between the sterols and the tetracyclic triterpenes is a matter mainly of origin
and custom. Spirostans, furostans, and many of the steroidal alkaloids have
structures which are formally derived from cholestanes by linking between two
side-chain sites, or between a side-chain and a skeletal carbon, via an oxygen
(epoxy) or nitrogen (epimino) bridge. Vitamin D3 and its analogues are 9,10-
secocholestanes. All of these classes are described separately below.
Alkylated cholestanes of many types occur widely in plants, fungi, and
marine organisms. The very large classes of 24-methylcholestanes (ergostanes
and campestanes) and 24-ethylcholestanes (stigmastanes and poriferastanes) are
sufficiently important that their parent hydrocarbons have been assigned these
special systematic names (not used in Chemical Abstracts however). They are
treated in separate sections below. The 4,4,14-trimethylcholestanes (lanostanes)
are covered in the preceding terpenoid section. Many alkylcholestane
derivatives, however, fall outside these major groups, and have not been
dignified by special class names. They are treated in DNP as derivatives of
cholestane. Others are homocholestanes, in which additional carbon atoms
lengthen the side-chain, rather than branching off it. Many of these unusual
sterols are best known by trivial names that reflect their biological origins.
The cholestan-26-oic (or 27-oic) acids (VT1100) form a small but significant
group of bile acids (see cholanes above).

Ergostane steroids (excluding withanolides and brassinolides)

(VT1300)
The 24-methylcholestane structure is termed either ergostane or campestane,
depending upon the configuration at C-24 although Chemical Abstracts indexes
campestanes as 24R-ergostanes. The Fieser convention (see above) defines
ergostanes as 24β-methylcholestanes; campestanes are 24α-methylcholestanes.
These stereochemical labels have the advantage of being unaffected by adjacent
substitution or unsaturation. While the saturated and ∆25-unsaturated ergostane
side-chanes have the 24S configuration, the altered priorities of groups around
C-24 give ergost-22-ene the 24R configuration.

141
 H H
H H
24 24
20 20

17
H H
17

H H
Ergostane Campestane

For historical reasons, most of the compounds of these classes have become
known as ergostane (or ergosterol) derivatives, even though, according to
current nomenclature, some of them should strictly be named as campestanes. In
DNP, therefore, ergostane-based nomenclature is generally given precedence,
with campestane synonyms added where appropriate.
A further complication, firmly rooted in historical precedent, is the use of the
locant C-28 for the carbon atom of the 24-methyl group. The latest IUPAC-IUB
recommendation is that the locant C-28 be reserved for the 4α-methyl group in
lanostanes, and in other 4,4-dimethylsterols of terpenoid type, with C-29 and C-
30 allocated, respectively, to the 4β- and 14α-methyl groups.* The locant C-28
has therefore acquired two distinct meanings, according to context. In DNP the
C-24 methyl group in ergostanes and campestanes retains its original locant as
C-28, allowing the use of derivative names containing such expressions as
ergost-24(28)-ene (for 24-methylenecholestanes) or ergostan-28-ol (for 24-
hydroxymethylcholestanes). The cholestane-based synonyms favoured by
IUPAC-IUB are also given, where necessary, for clarity.

28
CH2OH
H H
24

H H
24-Methylenecholestane 24-Hydroxymethylcholestane
[Ergost-24(28)-ene] (Ergostan-28-ol)

The C28 ergostane skeleton occurs in some other groups of compounds of

steroidal type, notably the withanolides and the brassinolides, which are highly
oxygenated ergostane derivatives (see below). Compounds of the Vitamin D2
class are 9,10-secoergostane derivatives (see Vitamin D, below). Ergostanes
with the 9β,10α-configuration, which are among the products of photochemical
transformation of ergosta-5,7-dienes, have commonly been named as
lumistanes, although this term is not recognised in the IUPAC-IUB rules for
nomenclature.

Stigmastane steroids (C29) (VT1550)

These are the 24-ethylcholestanes, stigmastanes and poriferastanes being
epimeric at C-24. The long history of stigmastane-based nomenclature, derived
from the common plant sterol Stigmasterol, has ensured that this is by far the

* The current IUPAC-IUB-recommended locant number for the 24-methyl carbon is 241,
applicable, for example, in listing 13C nmr assignments, but not recommended for use as a locant
for unsaturation or further substitution. In such cases the entire C-24 substituent should be appro-
priately named, e.g. as a 24-methylene or 24-(hydroxymethyl) derivative of the cholestane series.

142
more widely used of the two names, a situation paralleling that described above
for ergostanes and campestanes. In the Fieser system, stigmastanes have the
24α configuration, and poriferastanes are 24β. Again the sequence rule is
now preferred, with 24R or 24S depending upon local substitution and/or
unsaturation. Chemical Abstracts indexes poriferastanes asg 24S-stigmastanes.

H H
H H
24 24
20 20
H 17
H
17

H H
Stigmastane Poriferastane

As with ergostanes, common usage over several decades has favoured the
locants C-28 and C-29 for the two ethyl carbon atoms, and these are used here.
The IUPAC-IUB recommendation is that the two ethyl carbon atoms be desig-
nated 241 and 242 whenever locants are needed. Synonyms based upon 24-ethyl-
cholestane, 24-ethylidenecholestane, or 24-vinylcholestane are given in DNP
where suitable.

H H

H H
24-Ethylcholestane 24-Ethylidenecholestane

H
24-Vinylcholestane

Ecdysteroids (C27) (VT1150)

Ecdysteroids or ecdysones are moulting hormones of insects and crustaceans.
They have also been isolated from many plants. The first ecdysone to be
isolated was α-Ecdysone from the silkworm (Bombyx mori). Most ecdysteroids
have a 2β,3β,14α,20,22-pentahydroxy-5β-cholest-7-en-6-one skeleton with
further hydroxylation.

OH

OH

HO
OH
HO
H
O
α-Ecdysone

143
Grieneisen, M.L. (1994) Insect Biochem. Mol. Biol., 24, 115
Nakanishi, K. (1971) Pure Appl. Chem., 25, 167.

Spirostan and furostan steroids (C27) (VT1200, VT1250)

Many plant products belong to these related classes; a few of the spirostans,
notably Diosgenin and Hecogenin, are sufficiently plentiful to have become
major sources of steroidal intermediates for the synthesis of steroid hormones
and pharmaceutical analogues.
The furostans are 16β, 22-epoxycholestanes, the extra ring being labelled as
ring E. The parent structure furostan is defined as having the side-chain
configuration illustrated. The configuration at C-22 (when saturated) is indicated
according to the sequence rule. Those derivatives that are further substituted in
the side chain also require sequence rule designations, including C-25 if C-26 is
substituted. Some naturally-occurring furostan derivatives have additional epoxy
rings between pairs of carbon atoms in the side chain. The spirostans (below)
are a special case.
26
H H 23 25

24 27

O
H H
H
H H

H
Furostan

Spirostans are 16β,22 : 22,26-diepoxycholestanes, or 22,26-epoxyfurostans.

The sixth ring so formed is known as ring F. Chemically, the spiro centre at C-
22 has the character of an internal acetal derived from a 16β, 26-dihydroxy-
cholestan-22-one.
The parent name spirostan implies the configurations illustrated for C-20 and
C-22, but that at C-25, and any other chiral locations if ring F is substituted, are
given according to the sequence rule.
The omission of a terminal ‘e’ from the names furostan and spirostan
recognises that they are not hydrocarbons. Derivative nomenclature for these
classes of compounds, however, requires the addition of ‘e’ to the stem of the
name if a consonant follows, e.g. 5α-spirostane-3β,12β-diol.
Tetrahedral geometry at the spiranic C-22 causes ring F to lie perpendicular
to the general orientation of the other rings. Projection formulae onto the plane
of the paper fail adequately to express this stereochemical relationship, and lead
to difficulties in correctly illustrating the configurations of any substituents in
ring F. The IUPAC-IUB-recommended way of drawing the formula avoids this
problem by including a perspective representation of ring F, as shown below.
The particular chair conformation illustrated is a matter of convention, and does
not necessarily correspond to the preferred conformation in every case.

27

21
H O 26 25
F
20 23
24
E
O
H H
H
H H

H
Spirostan

144
Withanolide and brassinolide steroids (C28) (VT1400)
The withanolides are a group of naturally occurring plant steroids with an
ergostane skeleton and a side-chain δ-lactone ring linking C-22 and C-26. The
lactone ring is usually unsaturated at C-24, and there is a high level of
oxygenation in the skeletal rings, frequently including a 2-en-1-one system and
a 5,6-epoxide. The configurations are as shown below and the configuration at
C-22 is usually R.
28

27
24
23 25
22 26
O O
H

Withanolide

The Physalins are 13,14-secowithanolides with the formation of a 13,14- or

14,17-hemiacetal or acetal as in Withaphysalin C and Physalin B. Physalin B
also has a new carbon-carbon bond between C-16 and C-24.
Brassinolides are a group of plant growth promoting substances originally
isolated from rape pollen (Brassica napus) but now found to be widespread in
plants. They are highly oxygenated ergostane derivatives, characterised by the
expanded B-ring with incorporation of an oxygen atom to form an ε-lactone
ring (B-homo-7-oxaergostan-6-one derivatives). The lactone is not essential for
plant growth activity (Castasterone has an intact B-ring), but the 22R,23R-diol
system is.
The oxygenation pattern bears some relationship to the ecdysteroids but the
configurations at C-2,3 and 5 are α- in the brassinosteroids but are mostly β- in
the ecdysteroids.
Brassinolide

HO HO

OH OH
H H
HO HO
OH
HO O HO
H H
O O
Brassinolide Castasterone

Fujioka, S. et al. (1997), Nat. Prod. Rep., 14, 1.

Glotter, E. et al. (1991) Nat. Prod. Rep., 8, 415.
Kirson, I. et al. (1981) J. Nat. Prod., 44, 633.
Ray, A.B. (1994), Prog. Chem. Org. Nat. Prod., 63, 1.

Gorgostane and other cyclopropacholestane steroids (C30) (VT1700)

Gorgostane is the parent hydrocarbon of a widely-occurring group of sterols in
marine organisms. Its skeleton comprises ergostane with an additional methyl
group at C-23, and a methylene bridge between C-22 and C-23, forming a
cyclopropane ring. Configurations in the side chain are as illustrated unless
otherwise specified.
A wide variety of at least 100 diverse C30 and C31 marine sterols in the
gorgostane and related structural classes are known. Sponges are the most
prolific source. Sponge sterols are characterised by multiply alkylated side

145
chains, frequent presence of cyclopropane/cyclopropene functionality in the side
chain, and wide variation in the steroid A–D ring skeleton, including many
examples of A-nor and 19-nor variants.
H H
H 24
22
20 23

17

H
Gorgostane

D’Auria, M.V. et al. (1993) Chem. Rev., 93, 1839–1895.

Djerassi, C. et al. (1991) Acc. Chem. Res., 24, 371–378.
Faulkner, D.J. (1992) Nat. Prod. Rep., 9, 323–364.
Giner, J.L. (1993) Chem. Rev., 93, 1735–1752.

Vitamin D and related compounds (VT2850, VT2900)

The calcium-regulating vitamin D is found in two principal forms, vitamin D2
and vitamin D3, which differ only in the side chain. Vitamin D2, sometimes
called Ergocalciferol, is derived from the fungal sterol Ergosterol. Vitamin D3,
the natural mammalian form, is derived from cholesta-5,7-dien-3β-ol (7-
dehydrocholesterol), and is accordingly known also as Cholecalciferol. Other
compounds of the series are specified as belonging to either the ergostane or the
cholestane series by use of the appropriate numerical subscript (2 or 3). Both
forms of vitamin D arise from photochemical ring-opening of the unsaturated
ring B in the precursor sterol. The immediate products of ring-opening are
known as previtamin D2 or D3, respectively. The previtamin has a (6Z)-9,10-
seco-5(10),6,8-triene structure. Thermal rearrangement at physiological
temperature shifts the unsaturation in the previtamin to form the vitamin itself,
which has the (5Z,7E)-5,7,10(19)-triene structure. Metabolic changes in the liver
and the kidney lead to introduction of hydroxyl substitution at C-25 and C-1,
respectively, to give the active calcium-regulating hormones.
Formulae are usually drawn so as to represent the true elongated shape of the
vitamin D molecule. To reach this conformation, the molecule has to undergo
rotation around the 6,7-single bond within the triene system. This twisting
reverses the orientation of ring A with respect to the remaining rings, so the
normal meanings of α and β as applied to substituents in ring A become
confused. Unambiguous sequence rule descriptors are usually preferred (but not
by Chemical Abstracts), and are used in DNP. Thus the original 3β-hydroxy
group becomes 3S in the vitamin, whereas the important ‘1α’-hydroxylated
metabolites have the (1S,3R)-configuration. The sequence rule is also used,
when necessary, to describe configurations at any other chiral centres in ring A,
and at C-6 or C-7 in various reduced or oxidised derivatives of the triene
system, as well as for side chain substituents.

HO HO
7-Dehydrocholesterol Previtamin D3
(Cholesta-5,7-dien-3β-ol) (9,10-Secocholesta-5(10),6Z,8-trien-3S-ol)

146
 8

7
6

3
HO
Ergocalciferol; Vitamin D2
(9,10-Secocholesta-5Z,7E,
10(19)22E-tetraen-3S-ol)
HO
Cholecalciferol; Vitamin D3
(9,10-Secocholesta-5Z,7E,
10(19)-trien-3S-ol)

Anon (1985) Synform, 3, 75 (synth).

Coldwell, R.D. et al. (1990) Steroids, 55, 418.
Okuda, K.I. et al. (1995), J. Lipid. Res., 36, 1641.
Zhu, G.D. et al. (1995), Chem. Rev., 95, 1877 (synth).

147
Aminoacids and peptides (VV)
Aminoacids (VV0050–VV0140)
Protein α-aminoacids (VV0050)
The common α-aminoacids are characterised by the structure
RCH(NH2)COOH, where R is an aliphatic (including hydrogen), aromatic or
heterocyclic group. The exception is Proline, strictly an iminoacid, in which the
N atom is incorporated into a 5-membered pyrrolidine ring.
They are the primary products of nitrogen anabolism in plants, where they are
produced from ammonia (derived ab initio by nitrate reduction or nitrogen
fixation) by a process called the glutamate synthetase cycle. This produces
glutamate which is then transformed into the other aminoacids by a variety of
processes.
The aminoacids thus represent the most important nitrogenous component (in
terms of volume and accessibility) of the chiral pool produced by living
organisms and are of great importance in chiral synthesis.
Several hundred plant aminoacids are known. Of these, 20 only (known as
the primary protein aminoacids) are incorporated by all organisms into peptides
and proteins (not all of these 20 aminoacids can be biosynthesised by animals).
This protein synthesis occurs in the ribosomes by a process involving ribo-
nucleic acid (RNA), the nucleoside chain of which transmits the template
instructions of the DNA genetic material to the protein sequences, each primary
aminoacid in the chain being coded for by one or more nucleoside base triplets
or codons.
There is an IUPAC-IUB standard 3-letter code for each of the protein
aminoacids (as well as for the common nonprotein aminoacids). For ease of
computerised documentation of large peptide structures, one-letter codes have
more recently been introduced but these are not used in DNP as the full
structures of proteins and large peptides are not given in entries.

IUPAC-IUB
abbreviations
1. Alanine Ala A
2. Arginine Arg R
3. Asparagine Asn N
4. Aspartic acid Asp D
5. Cysteine Cys C
6. Glutamic acid Glu E
7. Glutamine Gln Q
8. Glycine Gly G
9. Histidine His H
10. Isoleucine Ile I
11. Leucine Leu L
12. Lysine Lys K
13. Methionine Met M
14. Phenylalanine Phe F
15. Proline Pro P
16. Serine Ser S
17. Threonine Thr T
18. Tryptophan Trp W
19. Tyrosine Tyr Y
20. Valine Val V
Aminoacids and their corresponding 3-letter and 1-letter codes

148
 Various posttranslational protein aminoacids known as secondary aminoacids
may then arise in the protein by various processes such as conjugation of OH,
SH or NH groups, N-methylation or hydroxylation (especially to produce 4-
Hydroxyproline). A special case of posttranslational change is the reversible
oxidation of cysteine residues to produce the disulfide Cystine thus linking
different parts of the peptide chain by disulfide bridges as part of the secondary
structure of the protein.
With the exception of Glycine, all of the genetically coded protein
aminoacids are chiral and belong to the L-series. In all cases except Cysteine,
this corresponds to (S-) according to the Cahn-Ingold-Prelog convention. In
Cysteine the higher priority of the CH2SH group over the COOH group
means that L- corresponds to (R-).
COOH

H2N C H
CH2SH
L-(≡R-)-Cysteine

Aminoacids of the opposite D-series can be detected in hydrolysates of aged

proteins in which they arise by slow racemisation (they are also produced as
artifacts of racemisation during acid or especially alkaline hydrolysis of
polypeptides). D-Aminoacids are common constituents of antibiotics and
bacterial proteins.
Barrett, G.C. (ed.) (1985) Chemistry and Biochemistry of the Amino Acids, Chapman &
Hall, London.
Coppola, G.M. and Schuster, H.F. (1987) Asymmetric Synthesis: Construction of Chiral
Molecules Using Amino Acids, Wiley, New York.
Hunt, S. (1991) in Methods in Plant Biochemistry, (ed. L.J. Rogers) Volume 5,
Academic Press, New York, pp. 1–52.
Williams, R.M. (1989) Synthesis of Optically Active Aminoacids, Pergamon, Oxford.

Non-protein α-aminoacids (VV0100)

In addition to the proteinaceous aminoacids, plants produce several hundred
known non-protein aminoacids which arise by a variety of metabolic routes.
Some of these have demonstrated functions, for example as defence chemicals;
the plant aminoacids probably perform a generalised nitrogen storage function.
A considerable number of atypical α-aminoacids have been isolated from
microbial sources. They inhibit the growth of a range of microorganisms but
their effects can be readily reversed by supplementing the growth medium by
the requisite principal aminoacid.
Atypical aminoacids are encountered in the hydrolysates of microbial peptide
antibiotics. These do not always occur in the free state but a number have been
included in DNP since a given aminoacid may be present in a range of different
peptides.

Hatanaka, S.I. et al. (1992) Prog. Chem. Org. Nat. Prod., 59, 1 (aminoacids from fungi).
Scannell, J.P. et al. (1974) in Chemistry and Biochemistry of Amino Acids Peptides and
Proteins, Dekker, New York (antimetabolites).

β-Aminoacids (VV0120)
A number of β-aminoacids occur naturally, especially in peptide hormones and
antibiotics. Of these the most widespread is β-Alanine.

Drey, C.N.C. (1985) in Chemistry and Biochemistry of the Amino Acids, (ed. G.C.
Barrett) Chapman & Hall.

149
Peptides (VV0150–VV0600)
Peptides are oligomers and polymers notionally derived from aminoacids by
condensation to produce amide linkages. The boundary between oligopeptides
and polypeptides is arbitrary and in DNP has been set at 10 aminoacid residues.
The configuration of aminoacid residues in polypeptides is assumed to be L-
when not indicated otherwise.
There is evidence that in higher organisms small peptides (hormones) can
arise only by cleavage of protein prohormones.
A large number of biologically-active atypical peptides have been isolated
from bacteria, actinomycetes and fungi. Structurally they represent an extremely
diverse group, encompassing those metabolites containing two or more
aminoacid residues linked by a peptide bond, but possessing some additional
features not characteristic of proteins. These may include unusual aminoacid
residues, protein aminoacids with the D-configuration or raised to a higher
oxidation level, or non-peptide linkages between residues (e.g. ester, lactone or
a γ-glutamyl amide). In addition the molecules may be linear or cyclic, contain
one or a combination of the above mentioned features, be modified by further
interactions between the side chains of amino-acid units within the peptide, or
conjugated with either lipids or sugar units.

Diketopiperazines (dipeptide anhydrides) (VV0150)

These are among the most numerous of all naturally occurring peptides. They
range from simple cyclic dipeptides to highly complex fused ring systems such
as the antiviral Bicyclomycin and the toxic 1,4-sulfur bridged Sporidesmins
and related compounds. The ergot peptides (listed in the alkaloid section) can
also be regarded as derivatives of cyclic dipeptides.
Nomenclature of the simple diketopiperazines is complicated by the
proliferation of different ways of naming them. In DNP, systematic Chemical
Abstracts names are used as their entry names, but the entries contain a full
range of possible synonyms.

Cyclic oligo-and polypeptides (VV0500)

No cyclic homodetic tripeptides with or without biological activity have been
observed to date. Cyclic peptides derived from 4–11 aminoacid residues linked
by peptide bonds have been isolated from a variety of microorganisms. Their
biological properties are diverse, ranging from antitumour activity for some
cyclic tetrapeptides, through to iron complexation for some hexapeptides, the
antibacterial properties of the Gramicidin and Tyrocidin decapeptides,
and the immunosuppressant activity of the undecapeptides of the Cyclosporin
family.

Depsipeptides (VV0600)
Cyclic heterodetic peptides or peptide lactones are those in which one or more
of the peptide bonds have been replaced by ester linkages. Valinomycin and
related antibiotics, though of no clinical value, are important biochemical tools
in that they specifically complex with alkali metal ions. The Actinomycin
family possess two peptide lactones attached to a common phenoxazine system
and form stable complexes with DNA by intercalation; they are used clinically
in the treatment of child leukaemia.

150
Large peptides and proteins (VV1000, VV2000)
Entries are given in DNP for the majority of bioactive peptides secreted by
plants and animals for which reasonable structural information exists, including
many insect neuropeptides which are an active field of research. Entries are
presented for the most important non-enzyme proteins and for some enzymes,
but full structures are not given in individual entries, the structures where
known can be assessed via the cited references.

Large modified peptides

This is rather an arbitrary group including all those peptide antibiotics with a Mr
greater than 1000. The development of sophisticated spectroscopic and
analytical methodology over the past decade has led to the isolation and
structural identification of a wide variety of highly modified peptides. The
peptaibol group of linear peptides exemplified by Alamethicin are characterised
by the presence of a large number of α-aminobutyric acid (aib) residues. These
antibiotics, which form ion channels in biological and artificial membranes, are
important biophysical tools. Thiostrepton and related antibiotics contain a
central pyridine or reduced pyridine entity of unknown origin, together with a
substantial number of cysteine derived thiazole units. The glycopeptides of the
Bleomycin family which also possess similar thiazole units display remarkable
antitumour activity. These molecules not only intercalate within double stranded
DNA but also have an iron binding site for carrying singlet oxygen. This is
positioned so as to effect oxidative cleavage of one of the DNA chains. Several
of the Bleomycins are used clinically. Semi-synthesis has been employed to
produce analogues for structure activity studies.
With such a diverse structural group it is impossible to provide an overview
of the biosynthesis, but so far, for the majority of the larger bacterial peptide
antibiotics investigated, such as the Gramicidins, Bacitracins and Polymyxins,
it is evident that they are not synthesised on ribosomes but via the so-called
multienzyme thiotemplate.

Bladon, C. (1993) in The Chemistry of Natural Products, 2nd edn (ed. R.H. Thomson)
Blackie, Glasgow, p. 183 (rev).
Fusetani, N. et al. (1993), Chem. Rev., 93, 1793–1805 (sponge peptides)
Gross, E. (ed.) (1983) The Peptides, Academic Press, New York (general).
Lipmann, F. (1980) Adv. Microbiol. Physiol., 21, 227 (biosynth).
Sammes, P.G. (1975) Prog. Chem. Org. Nat. Prod., 32, 51 (cyclodipeptides).

β-Lactams
Penicillins and cephalosporins (VV0700, VV0800)
These are by far the most important group of the β-lactam antibiotics.
The naturally-occurring penicillins are a closely related group of antibacterial
agents produced predominantly by fungi. They possess a common β-lactam-
thiazolidine fused system. The N-acyl side-chain, in which variation can occur,
is limited to a small number of aliphatic and aromatic groups.
The naturally-occurring cephalosporins which are produced predominantly by
Acremonium/Cephalosporium and Streptomyces spp. possess a common β-
lactam-dihydrothiazine fused system, but in this case the side-chain is limited to
an α-aminoadipoyl group.
All β-lactams act by inhibiting bacterial cell wall biosynthesis. They are, in
varying degrees, susceptible to the inactivating β-lactam enzymes present in
many pathogens. The penicillins and cephalosporins are biosynthetically related

151
to, and derived from, a common tripeptide precursor. The other groups appear to
be produced by alternative pathways involving either peptide or aminoacid
intermediates.

S S

N N
O O
β-Lactam-thiazoline β-Lactam-dihydrothiazine

Carbapenems (VV0900)
These are now a fairly substantial group of naturally-occurring bicyclic β-
lactams. In terms of chemical stability they are highly sensitive compounds but
nevertheless exhibit potent broad spectrum antibacterial activity. Due to the low
titre and difficulties with isolation from microbial sources the most promising
clinical candidate, Imipenem, is currently produced by total chemical synthesis.

N
O
Carbapenem nucleus

Monocyclic β-lactams (VV0920)

Monocyclic β-lactams, such as the monobactams and nocardicins, are bacterial
products with limited antibacterial activity. However notable synthetics based on
the natural system (e.g. Aztreonam) are potent antibiotics against gram negative
organisms.
OH
N
HOOC NH2
CONH
OH
O
N
O
COOH

Nocardicin A

Clavams (VV0950)
The so-called clavams are predominantly produced by Streptomyces spp. The
most important member of this group, Clavulanic acid, although exhibiting
limited antibacterial properties is a potent β-lactamase inhibitor and is used
clinically in combination with semisynthetic penicillins. The other naturally-
occurring clavams, which have the opposite chirality at the ring junction, lack
antibacterial properties but demonstrate some antifungal activity.
H
O CH2OH
N
O
COOH
Clavulanic acid

Allen, J.D. et al. (1986) Adv. Intern. Med., 31, 119 (β-lactams).
Baldwin, J.E. (ed.) (1983) Tetrahedron Symposium in Print No. 10, 39 (penicillins).
Barrett, G.C. (ed.) (1985) Chemistry and Biochemistry of the Amino Acids, Chapman &
Hall, London.
Bentley, P.H. et al. (eds), (1992) Recent Adv. in the Chem. of β-Lactam Antibiotics,
Proc. 4th Int. Symp., RSC, London.
Brennan, J. (1986) in Amino Acids Peptides and Proteins, specialist periodical reports,
RSC, London, 17, 171.

152
Brown, A.G. et al. (eds) (1985) Recent Advances in Chemistry of β-lactam antibiotics,
RSC Special Publication no. 52.
Bycroft, B.W. et al. (1987) Biotechnology Handbook, Vol. 1, (ed. J. Peberdy) Plenum
Press, New York, pp. 113.
Casy, A.F. et al. (1989) J. Pharm. Biomed. Anal., 7, 1121 (ms).
Demain, A.L. et al. (ed.) (1983) Antibiotics containing the β-lactam structure,
Handbook of Experimental Pharmacology, p. 67.
Frydrych, C.H. (1991) Amino Acids Pept., 22, 294; (1992) 23, 249.
Jensen, S.E. (1986) CRC Crit. Rev. Biotechnol., CRC Press, Boca Raton, 3, 277
(biosynth).
Kleinkauf, H. et al. (eds) (1990) Biochem. of Pept. Antibiot. Recent Adv. in Biotechnol.
of β-Lactams and Microbial Bioactive Pept., De Gruyter, Berlin.
Morin, R.B. et al. (1982) Chemistry and Biology of β-lactam Antibiotics, Vols 1–3,
Academic Press, New York (general).
Ono, H. et al. (1990) Biochem. Pept. Antibiot., 131.
O’Sullivan, J. et al. (1986) in Biotechnology, Vol 4, (ed. H. Page) VCH, Weinheim,
Ger., p. 247.
Parker, W. et al. (1986) Adv. Appl. Microbiol., 31, 181 (monobactams).
Robinson, J.A. et al. (1985) Nat. Prod. Rep., 2, 293 (biosynth).
Rolinson, G.N. (1986) J. Antimicrob. Chemother., 17, 5.
Salton, M.R.J. et al. (eds) (1981) β-Lactam antibiotics: Mode of Action, new
developments and future prospects, Academic Press, New York.
Stachulski, A.V. (1989) Amino Acids Pept., 20, 249; (1990) 21, 248.
Walsh, T.F. (1988) Annu. Rep. Med. Chem., 23, 121.
Williamson, J.M. (1986) CRC Crit. Rev. Biotechnol., 4, 111 (biosynth).

Glycopeptides (VV3000)
The members of the Vancomycin family are the most significant within this
relatively small and structurally self-evident category of antibiotics. Their
activity is restricted to gram-positive organisms but they are particularly
effective against the so-called multiresistant streptococcal and staphylococcal
strains and for this reason have found significant clinical application.

Egge, H. et al. (1987) Mass Spectrom. Rev., 6, 331 (ms).

Lancini, G. et al. (1990) Biochem. Pept. Antibiot., 159 (Vancomycins).
Williams, D.H. (1996) Nat. Prod. Rep., 13, 469 (rev).

153
Alkaloids (VX)
Alkaloids are a large group of nitrogen-containing secondary metabolites of
plant, microbial or animal origin. The term originally implied pharmacologically
active bases of plant origin, but the definition has subsequently been broadened
so that it is now generally considered to include the majority of nitrogen-
containing natural products with the exception of the simple aminoacids,
proteins and nitrogen-containing substances of polyketide origin such as the
aminoglycoside antibiotics. Basic properties may be weak or absent as in the
various types of amide alkaloids. The class of microbial alkaloid overlaps
considerably with that of the nitrogenous antibiotics, and substances such as the
cytochalasans which show antibiotic properties are in DNP classified as
alkaloidal, the definition being a matter of semantics.
Biogenetically and structurally the alkaloids are diverse and it is usual to
discuss them in terms of biogenetic origin rather than purely on the basis of
structural features. The organisation of alkaloid groups within the Type of
Compound Index follows the order given below.

Alkaloids derived from ornithine

Simple ornithine alkaloids (VX0300)
Several simple alkaloids derived possibly from ornithine are known. These
include Hygrine and Stachydrine. Condensation of two ornithine units with
acetoacetate gives Cuscohygrine. Other alkaloids containing a pyrrolidine ring
include Nicotine, Ficine (in which the pyrrolidine ring is attached to a flavone
nucleus), Macrostomine (in which it is attached to a benzylisoquinoline
skeleton), and Brevicolline (in which it is attached to a β-carboline unit).
Clearly the biogenesis of these molecules requires other precursors.
Macrostomine is presumably derived from tyrosine, just as Brevicolline has
been shown to be derived from tryptophan.

H2NCH2CH2CH2CHCOOH N CH2COCH3
NH2 Me
Ornithine Hygrine

Chromone alkaloids (VX0340, VX0350)

A structure consisting of a pyrrolidine, piperidine or pyridine ring linked to the
A ring of chromone is referred to as a chromone alkaloid. This group of
compounds can be sub-divided into two types, namely those in which the
chromone nucleus exists as Noreugenin (5,7-Dihydroxy-2-methylchromone) –
indexed in DNP as chromone alkaloids – and those which bear a phenyl
substituent at C-2 (indexed as flavonoid alkaloids). The former group is typified
by Rohitukine and Schumannificine. Typical flavonoid alkaloids include
Ficine and Vochysine. Compared with the noreugenin-related alkaloids, which
have only been isolated from the plant families Meliaceae and Rubiaceae, the
flavonoid alkaloids are more widely distributed throughout the higher plants.

154
 O O
HO
A
2
HO CH3
O O
Chromone Noreugenin

Tropane alkaloids (VX0400)

These are derived from ornithine and acetoacetate. Almost all of them are esters
of mono-, di-, and tri-hydroxytropanes. They are characteristic constituents of
the Solanaceae. Atropine and Cocaine are important representatives. Recent
evidence suggests that for some alkaloids (Cocaine and its close relatives)
malonylcoenzyme A is involved in the biosynthesis, rather than
acetoacetylcoenzyme A.
1 2
7
8 NMe 3
6
5 4

Tropane
8-Methyl-8-azabicyclo[3.2.1]octane, 9CI

Pyrrolizidine alkaloids (VX0440, VX0500, VX0520, VX0540)

These occur in species of the Senecio genus, and elsewhere in the Compositae
and Leguminosae. They have been shown to be responsible for the toxic effects,
particularly liver damage, in livestock grazing on pastures infested by these
species. Toxicity appears to be the result of oxidation in vivo to pyrrole
derivatives. The majority of pyrrolizidine alkaloids are either relatively simple
esters formed from a pyrrolizidine base, the necine, exemplified by Retronecine,
or more complex cyclic esters formed between a necine and a necic acid
(VX0500), an example being Monocrotaline. The necic acid units in this latter
and other diester alkaloids are themselves probably derived from an aminoacid
(e.g. isoleucine), rather than acetate or mevalonate.
HO H CH2OH

Retronecine

Many, and perhaps the majority, of pyrrolizidine alkaloids occur in the plant
as N-oxides, the N-oxide function being lost during isolation.

Miscellaneous ornithine-derived alkaloids (VX1160, VX1260)

Two other small groups of alkaloids may be derived from ornithine, but this
remains to be proved. The Stemona alkaloids, e.g. Tuberostemonine, contain a
pyrrolidine ring, possibly originating from ornithine, but the structure reveals
that its biosynthesis is complex. The Elaeocarpus alkaloids, e.g. Elaeocarpine,
may also originate from ornithine, together with a polyketide unit. Alternatively,
the whole skeleton may be polyacetate-derived. In the case of Elaeocarpidine,
tryptamine is also obviously implicated.

155
 O

O H
H
H HH
N H O O
H

Tuberostemonine

Gellert, E. (1982) Indolizidine Alkaloids, J. Nat. Prod., 45, 50.

Gellert, E. (1987) The Phenanthroindolizidine Alkaloids, in Alkaloids: Chemical and
Biological Perspectives (ed. S.W. Pelletier) Volume 5, Wiley-Interscience, New
York.
Herbert, R.B. (1985) The Synthesis of Indolizidine and Quinolizidine Alkaloids of
Tylophora, Cryptocarya, Ipomoea, Elaeocarpus, and related species, in Alkaloids:
Chemical and Biological Perspectives, (ed. S.W. Pelletier) Volume 3, Wiley-
Interscience, New York.

Alkaloids derived from lysine

Simple piperidine alkaloids (VX0620, VX0680)
These may be derived from lysine, acetate, acetoacetate, etc., in analogous
fashion to the simple pyrrolidine alkaloids. They include Pseudopelletierine,
Anabasine and Lupinine.
NMe
CH2OH
H
9 1
8 10 2
7 3
O 6 N 4

Pseudopelletierine Lupinine

All these structural types have their analogues among the pyrrolidine
alkaloids, and while it is tempting to assume biosynthesis from lysine it may not
in all cases be true; Coniine, for example, appears to be acetate-derived.

O
O N
O
Piperine

Relatively simple derivatives of piperidine include the alkaloids of black

pepper (Piper nigrum), e.g. Piperine.

Lobelia alkaloids (VX0660)

These have no analogy among the pyrrolidine alkaloids. An example is
Lobelanine.

More complex lysine-derived alkaloids (VX0900, VX0920, VX0940,

VX0960, VX0970, VX0980)
These include Cryptopleurine, the tri- and tetracyclic alkaloids of Cytisus and
other species of Leguminosae, e.g. Cytisine, the poisonous principle of the

156
laburnum, and the closely-related sparteine group (note tricky stereochemistry
owing to twofold rotation-reflection axis). Penta- and hexa-cyclic bases are
found in Ormosia species; of these Ormosanine is representative.
13 NH H 17 15
7 5 7 C
N 14
5 6 8 11 4 6 D 13
4 11
3 A B 12
9 3 9
2 N 10 2 N 10
H
O
(+)-Cytisine (–)-Sparteine

OMe
MeO
H

MeO

Cryptopleurine

Lycopodium alkaloids (VX1280)

These, such as Lycopodine, are constituents of the club mosses. Whereas the
earliest proposal concerning their biosynthesis implicated two C8 units derived
from acetate, it has more recently been established that two lysine units are
involved. Numerous skeletal variants are known, all of which can be related to
the Lycopodine skeleton; examples are Fawcettidine and Serratinine.

8
15
12 7
10 6
14 5
9 13
N 4 O
1 3
2

Lycopodine

Lythraceae alkaloids (VX0760)

These are characterised by several unusual structural features. Lythrancine
contains a quinolizidine ring system attached to a diphenyl residue, one of the
benzene rings in which is derived from cinnamic acid. Other alkaloids in this
group contain a diphenyl ether grouping, e.g. Decaline, and others a piperidine
ring instead of a quinolizidine ring, e.g. Lythranidine. The biosynthesis of these
alkaloids involves lysine as source of the quinolizidine or piperidine ring, and
phenylalanine as precursor of one of the aromatic rings. The numbering system
adopted throughout DNP for lactonic Lythraceae alkaloids (e.g. Decaline) is the
one generally accepted. This was introduced by Horsewood et al (Can. J.
Chem., 1979, 57, 1615) and corresponds closely to that introduced by Fujita et
al for piperidine and quinolizidine metacyclophane alkaloids (e.g. Lythranidine,
Lythrancine). The carbon atoms that correspond in biogenetic origin to the three
types thus maintain corresponding numbers. Note that CA numbering is
different.

157
 MeO 17
HO OMe
MeO 18 14 21 17
21 13 20 18
20 14
24 12
10 11 1 13

OH 2 12
1 9 OH HO
2 N 3
H
11
3
H 5
H 4
N 10
4 6
HO H 5 9
H H
HO
Lythrancine Lythranidine

O
12
H 11
O
5 3 13
H
N 14
1

O
23
MeO
OMe
Decaline

Blumenkopf, T.A. and Heathcock, C.H. (1985) Synthesis of Lycopodium Alkaloids, in

Alkaloids: Chemical and Biological Perspectives (ed. S.W. Pelletier, Vol. 3, Wiley-
Interscience, New York.
Elbein, A.E. and Molyneux, R.J. (1987) The Chemistry and Biochemistry of Recently
Isolated Indolizidine Alkaloids, in Pelletier, Vol. 2.
Fodor, G. and Colasanti, B. (1985) The Pyridine and Piperidine Alkaloids: Chemistry
and Pharmacology, in Pelletier, Vol. 3.
Fujita, E. and Fuji, K. (1976) The Lythraceous Alkaloids, in MTP Series 2, Vol. 9,
Alkaloids, (ed. K. Wiesner), Butterworths, London.
Herbert, R.B. (1985) The Synthesis of Indolizidine and Quinolizidine Alkaloids of
Tylophora, Cryptocarya, Ipomoea, Elaeocarpus, and Related Species, in Pelletier,
Vol. 3.
Kinghorn, A.D. and Balandrin, M.F. (1984) Quinolizidine Alkaloids of the
Leguminosae: Structural Types, Analyses, Chemotaxonomy, and Biological
Properties, in Pelletier, Vol. 5.
Valenta, Z. and Liu, H.J. (1976) The Ormosia Alkaloids, MTP Series 2, Vol. 9,
Alkaloids.

Alkaloids derived from nicotinic acid (VX1020)

This is a relatively small group. Nicotine and Anabasine are presumably
derived from nicotinic acid and ornithine or lysine, respectively. However, the
piperidine ring in Anatabine, from Nicotiana glutinosa, appears not to be
derived from lysine or from a polyacetate precursor; instead, both rings are
derived from nicotinic acid. Arecoline, from betel nuts, and Ricinine, from the
castor oil plant, are clearly derivable from nicotinic acid; in the case of Ricinine
this has been established. Dioscorine, from Dioscorea hispida, provides a
fascinating example of the unexpected in alkaloid biosynthesis. At first sight it
seems plausible to postulate that it may be formed from lysine and a polyketide
fragment. However, lysine is not a precursor, and it would appear that
Dioscorine is formed from nicotinic acid and, probably, a polyacetate unit.

N Me
Nicotine

158
Fodor, G. and Colasanti, B. (1985) The Pyridine and Piperidine Alkaloids: Chemistry
and Pharmacology, in Alkaloids: Chemical and Biological Perspectives, (ed. S.W.
Pelletier) Vol. 3, Wiley-Interscience, New York.
Leete, E. (1983) Biosynthesis and Metabolism of the Tobacco Alkaloids, in Pelletier,
Vol. 1.

Alkaloids of polyketide origin (VX0680, VX0700, VX1120,

VX1240)

Numerous alkaloids are derived from polyacetate precursors, together with one
or more amino acids. A few alkaloids, however, are almost entirely acetate-
derived. These include Coniine, from hemlock; this, perhaps surprisingly, is not
derived from lysine. Similarly, Pinidine, from Pinus sabiniana, is acetate-
derived. Other piperidine derivatives with side-chains at position 2, which may
be acetate-derived, although proof is at present lacking, include Nigrifactine
from Streptomyces species, Carpaine and Cassine.

N
H
Coniine

More complex examples include Coccinellin, the defensive agent of the

common ladybird, Coccinella septempunctata, Porantherine, from the shrub
Poranthera corymbosa, and the alkaloids of the Ancistrocladine group.
Still more complex are the Galbulimima alkaloids, e.g. Himbacine, which
may be formed from a nonaketide unit plus acetoacetate.

Naphthalene-isoquinoline alkaloids (VX1140)

This group comprises some forty alkaloids which have been isolated mainly
from the plant family Ancistrocladaceae, with some isolations from the
Dionchophyllaceae. Several skeletal types are known and are based on the point
of linkage between the two ring systems, e.g. 5,1′-coupled alkaloids
(Ancistrocladine, Dionchophylline C), 5,8′-coupled (Korupensine A), 7,1′-
coupled (Ancistrocladisine, Dionchophylline A), 7,2′-coupled
(Ancistrocladidine), 7,6′-coupled (Dionchophylline B), etc. The recently
isolated Michellamines are the first ‘dimeric’ alkaloids of this class to be
discovered.
These alkaloids are chiral not only due to diastereoisomerism at the methyl
groups but also in the biaryl linkage due to restricted rotation.
MeO OMe

CH3

HO 6
1 NH
MeO

Ancistrocladine

Cytochalasan alkaloids (VX1300)

Cytochalasins are metabolites of several different and unrelated fungi. They are
characterised structurally by the presence of a perhydroisoindolone system fused

159
to a macrocyclic ring of 11, 13 or 14 atoms. The macrocycle may be a
carbocycle, a lactone or a carbonate. In addition the isoindole ring carries either
a phenyl or an indolyl substituent at position 10; the latter group includes the
Chaetoglobosins.

18

O O O
13 23 13 22 13 20
O O O
8
O O 21
9 1 1 1
6 N 6 N 6 N
5 3 5 5
12
10 10 10
11
Lactone Carbonate Carbocycle

Biosynthetically, cytochalasins arise from phenylalanine or tryptophan and a

polyketide derived from acetate and methionine. Cytochalasins possess a range
of distinctive biological properties. These include inhibition of cytoplasmic
cleavage leading to polynucleate cells, nuclear extrusion and the inhibition of
cell mobility.

Binder, M. et al. (1973) Angew. Chem. Internat. Ed. Engl., 12, 370.
Cole, R.J. (1981) Toxic Fungal Metabolites, Academic Press, New York.
Dyke, H. et al. (1986) J. Chem. Soc. Chem. Commun., 1447 (synth).
Fodor, G. and Colasanti, V. (1985) The Pyridine and Piperidine Alkaloids: Chemistry
and Pharmacology, in Alkaloids: Chemical and Biological Perspectives, (ed. S.W.
Pelletier), Vol. 3, Wiley-Interscience, New York.
Jones, R.C.F. (1984) Nat. Prod. Rep., 1, 97.
Jones, T.H. and Blum, M.S. (1983) Arthropod Alkaloids: Distribution, Functions, and
Chemistry, in Pelletier, Vol. 1.
Pendse, G.S. (ed.) (1987) Recent Advances in Cytochalasans, Chapman & Hall,
London.
Turner, W.B. (1983) Fungal Metabolites II, Academic Press, New York.

Alkaloids derived from anthranilic acid

A number of diverse structural groups belong in this category, the major ones
being the quinolone, furanoquinoline, pyranoquinoline, acridine and quinazoline
groups.

Simple anthranilic acid derivatives (VX1460)

This small group includes Damascenine from Nigella damascena.
Biosynthetically the alkaloid is derived from anthranilic acid (chorismate-
derived), which is then hydroxylated and methylated.

COOMe
NHMe
OMe
Damascenine

160
Simple quinoline alkaloids (VX1480, VX1520, VX1540, VX1560,
VX1580)
These include Echinopsine and the phenethyl-quinoline, Cusparine.
O
4
5 3
6
7
8 1 2
N
Me
Echinopsine

In simple quinolone derivatives C-2 and C-3 are derived from acetate;
introduction of a prenyl group at C-3 followed by cyclisation then gives a
furanoquinoline, e.g. Platydesmine, or a pyranoquinoline alkaloid, e.g.
Flindersine. Interestingly, Dictamnine, from Dictamnus albus, appears to be
formed by loss of acetone from an oxidation product of Platydesmine.

OMe
5 4 3
6
7 2
8 1
N O
Dictamnine

Quinazoline alkaloids (VX1600)

These include Vasicine, from Adhatoda vasica, and Rutaecarpine, from Evodia
rutaecarpa; this latter base is clearly also derived from tryptophan. The
Tryptoquivalines, which are toxic metabolites from Aspergillus clavatus, are
also derived from anthranilic acid and tryptophan precursors, together with
(presumably) valine and methylalanine-derived units.
Macrorine, from Macrorungia longistrobus, is obviously derived from
anthranilic acid and histidine.

AcO H
N
O H
N
N
O O
N H
Vasicine NOH
N
O

Tryptoquivaline

Acridone alkaloids (VX1620)

These can be broadly divided into two main subgroups. The simple acridones
may be exemplified by Melicopidine and Melicopicine, and the
prenylacridones in which a prenyl group introduced into the acridone nucleus is
cyclised to give a pyran ring, by Acronycine.

O
OMe

N O
Me

Acronycine

161
Acridone-coumarin alkaloid dimers (VX1690)
The isolation in 1990 of the Acrimarines represented the first examples of
acridone-coumarin dimers from natural sources. To date, some twenty
compounds have been reported from Citrus plant (Rutaceae) roots.

1,4-Benzoxazin-3-one alkaloids (VX1720)

2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (known as DIMBOA)
is representative of this significant, yet often neglected group of alkaloids which
have plant hormone significance. They usually occur in the plant as glucosides
but cell injury apparently releases a glucosidase which catalyses hydrolysis to
the 2-hydroxy derivatives.
OH
N O

MeO O OH
DIMBOA

Benzodiazepine alkaloids (VX1760)

Cyclopenin and Viridicatin, from Penicillium cyclopium and P. viridicatum,
are clearly derived from anthranilic acid and phenylalanine. Apparently no plant
alkaloids with this skeleton are known to date.

Saxton, J.E. (1973) in The Acridines, 2nd edn (ed. R.M. Acheson), Wiley-Interscience,
New York.

Cryptolepine-type alkaloids (VX1800)

Cryptolepine (5-Methyl-5H-quindoline) is the most prominent representative of
this small but growing group of about ten related natural products isolated from
Cryptolepis spp. The parent compound, 10H-Indolo[3,2-b]quinoline
(Quindoline), has itself been isolated from C. sanguinolenta. More recently a
spiro-alkaloid (Cryptospirolepine), several cryptolepine isomers (e.g.
Isocryptolepine, Neocryptolepine, Cryptosanguinolentine, Cryptotackieine),
Hydroxycryptolepine, Cryptoheptine and three dimers (Biscryptolepine,
Cryptomisrine and Cryptoquindoline) were isolated, although the latter
alkaloid was shown to be an artifact. No biosynthetic studies of this skeleton
have been reported but a derivation from indole and N-methylanthranilic acid
could be imagined for cryptolepine.
4 N 6
3 5
7
2 8
1 11 10 9
N
H
Quindoline

162
Alkaloids derived wholly or in part from phenylalanine
or tyrosine
This extremely large and varied category consists of several different structural
types, which range from simple β-phenylethylamine derivatives to the much
more complex structures exemplified by the alkaloids of the Amaryllidaceae and
the bisbenzylisoquinoline alkaloids. The isoquinoline derivatives themselves
consist of a large number of structural types, which can be divided into upwards
of 20 sub-groups.

Simple tyramine alkaloids (VX2000)

The simplest derivatives of phenylalanine or tyrosine are the β-phenyl-
ethylamines, which are presumably obtained by decarboxylation and obvious
oxidative/alkylation stages.
The alkaloids in this group can be divided into four categories:
(a) those with a simple β-arylethylamine structure, e.g. Mescaline;
OR

(b) those with the structural unit ArCHCH2N<, e.g. Macromerine;
(c) the Ephedra bases, e.g. Ephedrine;
(d) miscellaneous alkaloids, e.g. Aurantiamide.

Cinnamic acid amides (VX2020)

Fagaramide, Herclavine and Subaphylline are simple members of this series.
These amides are all derived from a trans-cinnamic acid; Astrophylline is an
example of an N-cis-cinnamoyl derivative.

Securinega alkaloids (VX2100)

This small group of about 30 alkaloids occurs in the genus Securinega (fam.
Euphorbiaceae). The biosynthesis of these alkaloids, which is not readily
apparent, has been shown to involve tyrosine and lysine, in the case of
Securinine. Presumably Norsecurinine is derived from tyrosine and ornithine.
O

O 12
H
3
2
8 14
6 N
7 15

Securinine
Phyllanthidine is presumably an oxidative transformation product of
Allosecurinine, the diastereoisomer of Securinine, which also occurs naturally.

Betalain alkaloids (VX2140)

This is a group of some 50 alkaloidal pigments whose distribution is limited to
the order Centrospermae. As a group they are zwitterionic and water soluble.
Betanidin and Indicaxanthin are typical examples.

The Isoquinoline alkaloids

This extremely large and enormously varied group can be divided into
approximately twenty categories.

163
Krane, B.D. et al. (1982) J. Nat. Prod., 45, 377.
Menachery, M.D. et al. (1986) J. Nat. Prod., 49, 745.
Phillipson, J.D., Roberts, M.F. and Zenk, M.H. (eds) (1985) The Chemistry and Biology
of Isoquinoline Alkaloids, Springer Verlag, Berlin.
Shamma, M. (1972) The Isoquinoline Alkaloids, Academic Press, New York.
Shamma, M. and Moniot, J.L. (1978) Isoquinoline Alkaloid Research, 1972–1977,
Plenum Press, New York.

Simple isoquinoline alkaloids (VX2200, VX2300)

These can be further sub-divided into (a) those not bearing a carbon substituent
at C-1, and which are basic, e.g. Anhalamine; (b) those with an amide carbonyl
group at C-1, and therefore non-basic, e.g. Corydaldine; (c) those with a
methyl group at C-1, e.g. Salsoline; (d) those with a 1,2,3,4-tetrahydroiso-
quinolinequinone moiety, e.g. Mimosamycin, Renierone, and the more com-
plex group of Saframycin- and Renieramycin-type antibiotics; and (e)
miscellaneous bases.

Benzylisoquinoline alkaloids (VX2320)

The simple benzylisoquinoline skeleton is derived from two molecules of
tyrosine, and is the parent skeleton of a wide variety of alkaloids belonging to
numerous different ring systems.
The alkaloids with the unmodified benzylisoquinoline skeleton may be
divided into five subgroups; (a) 1,2,3,4-tetrahydrobenzylisoquinolines, e.g.
Reticuline – of central importance in the elaboration of other alkaloids; (b)
alkaloids in which all the rings are aromatic, e.g. Papaverine; (c) the cularines
(VX2440), which contain an oxepine ring between C-8 and C-2′; (d) alkaloids
with a carbon substituent at C-2′, such as Canadaline. These may be regarded
as ring-opened berberines; (e) benzylisoquinolines in which a pyrrolidine ring is
attached to C-4, e.g. Macrostomine.
4
5 3
MeO 4 6
5 3 7 2
6
7 2 MeO 8 1 NMe
HO 8 1 NMe
H
H O
HO 3′
2′ 1′ 2′ 1′
4′ 3′ 6′
MeO 5′6′ 4′ 5′
MeO OMe
Reticuline
Cularine

Gözler, B. and Shamma, M. (1984) J. Nat. Prod., 47, 753.

Pseudobenzylisoquinoline alkaloids (VX2330)

The term pseudobenzylisoquinoline alkaloid is used to describe a
benzylisoquinoline skeleton in which the pendant aromatic ring is oxygenated at
C-2′, C-3′ and C-4′. These alkaloids are derived biogenetically from
protoberberinium salts by C8-C8a bond scission. Polycarpine, Taxilamine and
Ledecorine are typical examples.
MeO
MeO NCHO
OH
OMe
OMe

Polycarpine

164
Bisbenzylisoquinoline alkaloids (VX2340–VX2430)
This very large group of alkaloids is composed of two benzylisoquinoline units
attached to each other by one, two, or three bonds. In most cases the units are
joined via ether linkages, but carbon-carbon bonds between the benzyl groups
are also known. The monomeric units involved are mainly hydroxylated or
methoxylated benzylisoquinolines, but aporphine units occur in more than 50
alkaloids, and a few alkaloids contain a proaporphine component. The alkaloids
may be subdivided into the five following major groups (the classification,
proposed by Shamma, contains at least 28 subgroups, all of which are composed
of unmodified benzylisoquinoline units. Dimeric alkaloids containing aporphine,
proaporphine, or otherwise modified benzylisoquinoline components are not
included here).

(a) Alkaloids containing aryl links only. (VX2340) The bark of Popowia
pisocarpa has yielded a group of seven alkaloids which contain a single
aromatic linkage between C-11 and C-11′. These include Pisopowetine and
Pisopowiaridine
(b) Alkaloids containing one ether link. (VX2360) This is the most
common structural type, the ether linkage being in most cases between C-11 and
C-12′, as in Dauricine.
4
5 OMe MeO 5′ 4′
6 6′
7 7′
MeN 1 8
OMe MeO 8′ 1′ NMe
H H
10 10′
11 11′
14 12 O 12′ 14′
13 13′
OH
Dauricine

However, other attachments are known, e.g. between C-11 and C-10′, as in
Vanuatine, between C-10 and C-7′, as in Malekulatine and Ambrinine, and
between C-11 and C-7′, as in Neferine.
(c) Alkaloids containing one aromatic link and one or two ether links.
(VX2370, VX2390) These alkaloids are mainly based on the Rodiasine and
6′,7-didemethoxy-6′,7-epoxyrodiasine skeleton, e.g. Tiliacorine.

5 OMe MeO 5′ 4′
18 6′ 18′
7′
MeN 1 8
OMe 8′ 1′ NMe
H O H
10 10′
14 12 12′ 14′
13 OMe HO 13′

Rodiasine, 9CI

(d) Alkaloids containing two ether links. (VX2380) The largest single sub-
group containing two ether linkages possesses the berbaman skeleton,
exemplified by Berbamine, which contains ether linkages between C-8 and C-
7′, and between C-11 and C-12′.

4 5 5′ 4′
6 6′
7 7′
HN 1 8 8′ 1′ NH
H O H
10 14′
11 13′
14 12 O 12′ 10′
13 11′

Berbaman, 9CI

165
 Almost as large as the berbaman group is the oxyacanthan group, e.g.
Oxyacanthine, which contains ether linkages between C-8 and C-7′, and
between C-12 and C-13′. Smaller groups include the Thalicberan (C-8 to C-6′
and C-11 to C-12′), Thalidasan (C-8 to C-5′ and C-11 to C-12′), and Thalman
(C-7 to C-5′ and C-11 to C-12′) types.

5 6′ 5′
6
7 7′ 8′
HN 1 8 1′ NH
H O H
1011 O 13′
14′
14 12 12′ 10′
13 11′

Oxyacanthan, 9CI

All these types contain ether linkages between the benzyl rings and between
the aromatic rings of the tetrahydroisoquinoline component. The Tubocuraran
sub-group contains ether linkages between the benzyl ring of one unit and the
aromatic ring of the isoquinoline component of the other unit. Other linkages of
this kind between benzyl and isoquinoline rings are also known.
5 5′
6 O 6′
7 7′
HN 1 8 8′ 1′ NH
H H
10 14′
11 13′
14 12 O 12′ 10′
5 13 11′
6 6′ 5′
7 7′ 8′
HN 1 8 O 1′ NH Thalman, 9CI
H H
1011 14′
13′
14 12 O 12′ 10′ 6
5
13 11′ 7
8 1 NH
Thalicberan, 9CI O H
12′ 14 10
5 6′ 5′
6 13 11
HN 8
7 O 7′ 8′ NH
12
1 1′
H H H O
14′ 1′
1011
13′ HN 8′
14 12 O 12′ 10′
7′
6′
13 11′ 5′

Thalidasan, 9CI Tubocuraran, 9CI

(e) Alkaloids with three ether links. (VX2400) These include alkaloids with
6′,7-epoxyoxyacanthan (e.g. Trilobine), 7,8′-epoxyoxyacanthan, and 8,12′-
epoxytubocuraran skeletons.
(f) Benzylisoquinoline-Aporphine dimers. (VX2700) Some alkaloids
consist of a benzylisoquinoline unit attached to an aporphine unit, via a single
ether linkage. Of these, Thalicarpine is typical.
(g) Miscellaneous bisbenzylisoquinoline alkaloids include those containing
a dienone ring in one of the isoquinoline components (e.g. Repanduline), some
with an aporphine unit attached to a pavine component, e.g. Pennsylpavine,
those with degraded benzylisoquinoline units (e.g. Baluchistanamine) or with a
proaporphine unit (e.g. Epiberbivaldine), and Cancentrine, which is really a
combination of cularine and morphinan components.

Guha, K.P. et al. (1979) J. Nat. Prod., 42, 1.

Guinaudeau, H. et al. (1984) J. Nat. Prod., 47, 565.
Schiff, P.L. J. Nat. Prod., 1983, 46, 1; 1987, 50, 529; 1991, 54, 645.
Schiff, P.L. (1987) in Alkaloids: Chemical and Biological Perspectives, (ed. S.W.
Pelletier), Vol. 5, Wiley-Interscience, New York.
Schiff, P.L. (1997) J. Nat. Prod., 60, 934.
Shamma, M. and Moniot, J.L. (1976) Heterocycles, 4, 1817.

166
Shamma, M. and Moniot, J.L. (1978) Isoquinoline Alkaloid Research, 1972–1977,
Plenum Press, New York.

Secobisbenzylisoquinoline alkaloids (VX2430)

The secobisbenzylisoquinolines are alkaloids in which one of the benzyliso-
quinoline units is cleaved between the C-1 and the α-carbon atom. A typical
example is Baluchistanamine, the apparent biogenetic precursor of which
appears to be Oxyacanthine.
With regard to the oxidation state of the C-1 and Cα-atoms, secobisbenzyliso-
quinoline alkaloids are aldehyde lactams (e.g. Baluchistanamine, Punjabine),
lactam esters (e.g. Gilgitine, Talcamine) or aldehyde amines (Jhelumine,
Chenabine). Karakoramine lacks the lactam moiety but possesses a hydroxy-
methyl function in the C′-aromatic ring.
Like the bisbenzylisoquinoline precursors, these alkaloids differ in the
number and position of the diphenyl ether linkages. Karakoramine has only one
such bond, Baluchistanamine has two, and Punjabine has three. Secantioquine
and Secolucidine are examples of a biphenyl system.
OMe MeO OMeO
MeN OMe NMe MeN NMe
H O H O
O O
HO O CHO
CHO HO
O
Baluchistanamine Punjabine

OMe MeO MeO

MeN HO NMe HO NMe
H O H
O CHO OH
HO HOH2C
O
Jhelumine Karakoramine

OMe O

NMe
O
H O
N
CHO
Me

OMe HO
Secolucidine

Cularine group alkaloids (VX2440)

The cularines are tetracyclic isoquinoline alkaloids which contain a dihydro-
oxepine or oxepine ring between C-8 and C-2′. They are formed by intra-
molecular oxidative coupling of 7,8,3′,4′- or 7,8,4′,5′-tetraoxygenated
tetrahydrobenzylisoquinolines (classical cularines and isocularines respectively)
although the biogenesis of the recently isolated Gouregine probably proceeds
via oxidation of an aporphine precursor. Structural variants in this group of
alkaloids include 4-hydroxycularines (e.g. 4-Hydroxysarcocapnine), oxo-
cularines (e.g. Oxocularine), 3.4-dioxocularines (e.g. Yagonine) and
Aristoyagonine, the only example of an aristocularine. Note the parallism
between cularine and aporphine alkaloids.

167
Secocularine alkaloids (VX2450)
The secocularines can be divided into two sub-groups, namely B- and C-ring
secocularines. B-Ring secocularines, exemplified by Secocularine, Secocul-
aridine and Norsecocularine, are structurally related to phenanthrene alkaloids
derived from aporphines and are probably formed in vivo by Hofmann
degradation of cularines. C-Ring cularines, represented by Noyaine, constitute a
new type of alkaloid without counterpart among aporphinoids.
NMe2

HO MeO NMe

O O O
COOMe

MeO OMe MeO OMe

Secocularidine Noyaine

Cancentrine-type alkaloids (VX2460)

These alkaloids are dimers involving a cularine unit linked to a morphinan unit
through a spiro bridge. They were found in a Dicentra species. Currently three
examples are known: Cancentrine itself and Dehydrocancentrines A and B.

MeO

O
NMe
O 14 H
8

MeO N
32
HO 31
O
MeO

Cancentrine

Quettamine alkaloids (VX2470)

Whereas classical-type cularine alkaloids of the Fumariaceae are biogenetically
derived from intramolecular oxidative coupling of tetraoxygenated tetrahydro-
isoquinoline precursors, the quettamines are obtained from in vivo intra-
molecular oxidation of a trioxygenated tetrahydroisoquinoline. So far only three
naturally occurring quettamines are known: Quettamine, Secoquettamine and
Dihydrosecoquettamine. These alkaloids, all found in Berberis baluchistanica,
incorporate either a benzofuran or a dihydrobenzofuran ring within the
molecular framework and the seco bases possess the N,N-dimethylaminoethyl
substituent.

+
MeO NMe2

OH

Quettamine

Dibenzopyrrocoline alkaloids (VX2480)

These alkaloids, only a few of which are known, are clearly derived by
oxidation of a benzylisoquinoline precursor; indeed, the ring system was
prepared in vitro by this route before it was encountered in nature.

168
 MeO
7 Me
HO 13 N
+ OMe
H
OMe
Cryptaustoline

Pavine and isopavine alkaloids (VX2520, VX2540)

These alkaloids are formed by alternative modes of oxidative cyclisation of
benzylisoquinoline precursors. In addition there are bisbenzylisoquinoline
alkaloids composed of pavine and aporphine units, e.g. Pennsylpavine.

MeO 4 5 6
3 OMe
7 8
2
MeO 1 NR
b 10 9 OMe
12
a 11
MeO a
Pavine R = H
HO NMe Argemonine R = Me

OMe
OH
b
Reticuline

O 4 5
3 6 7 8 OMe
2
O
1 12 NMe 10 9 OH
11

Amurensine
(Isopavine type)

Gözler, B. et al. (1983) J. Nat. Prod., 46, 293.

Proaporphine alkaloids (VX2600)

This group of alkaloids, e.g. Orientalinone, represents an intermediate stage in
the conversion of the benzylisoquinoline alkaloids by phenol oxidative coupling
into the aporphines.
RO
HO NMe
H

HO
OR

MeO 3 4
2 5
1
HO 6a NMe
7 H Aporphine skeleton
12
MeO 11 8
10 9

O
Orientalinone

The spirocyclohexenone ring may occur in various oxidation levels from

cyclohexadienone to cyclohexanol.

169
Aporphine alkaloids (VX2610, VX2620, VX2640, VX2700, VX2750,
VX2780, VX2800, VX2820, VX2840, VX6820, VX6840)
This large group of alkaloids simply contains the tetracyclic ring system formed
by phenol oxidative coupling of a benzylisoquinoline precursor. The structural
variations include:
(a) the simple aporphines, exemplified by Glaucine;
MeO 4
3 5
2
1
MeO 6a NMe
7
H
11
10
MeO 9 8
OMe
Glaucine

(b) dehydro derivatives of (a), in which the double bond is generally between
C-6a and C-7 in N-methyl compounds and between C-6a and N in apo
compounds;
(c) miscellaneous oxidative derivatives of (a), mostly with a hydroxy or
methoxy function at C-7, or two at C-4 and C-7;
(d) those with an aromatic isoquinoline ring and a carbonyl group at C-7, e.g.
Liriodenine, the so-called oxoaporphines;
(e) miscellaneous aporphinoids. Included in this group are Telezonine,
duguenaine-type aporphinoids, ring A quinonoid aporphinoids (e.g.
Pancoridine), oxoisoaporphines (e.g. Menisporphine), azafluoranthenes (e.g.
Rufescine), diazafluoranthenes (e.g. Eupolauridine), 1-azaoxoaporphinoids
(e.g. Sampangine), azahomoaporphines (e.g. Dragabine), so-called catechol
dioxygenase oxidized aporphinoids (e.g. Andesine, Chiloenine,
Santiagonamine), tropoloisoquinolines (e.g. Imerubrine) and Cleistopholine-
and Onychine- type alkaloids.
(f) compounds in which the heteroring has opened to give phenanthrene
derivatives, with the CH2CH2NR1R2 chain still present, e.g. Taspine;
(g) compounds derived from (f) which have lost C-5, mostly containing a
five-membered lactam ring (the aristolactams, e.g. Cepharanone A). The class
even includes some members in which nitrogen has been oxidised to a nitro
group, e.g. Aristolochic acid A.

O
O 2 1
3
4 NH
O 10
9

5
7 8

Cepharanone A

Although the aristolochic acids and aristolactams are non-basic they are still
classified as alkaloids since their respective skeletons bear a distinct
resemblance to that of the aporphines.
(h) a group of dimeric aporphinoid alkaloids exemplified by the aporphine-
benzylisoquinoline dimers, e.g. Thalifaberine, the proaporphine-
benzylisoquinoline dimers (e.g. Pakistanamine), and the Hernandaline-type
and Coyhaiquine-type alkaloids. The two latter types are, respectively,
oxidation products of the aporphine-benzylisoquinolines and proaporphine-
benzylisoquinolines.
A new addition to this class of compound are the proaporphine-tryptamine
dimers. These heptacyclic alkaloids, found in Roemeria hybrida (Papaveraceae)

170
and Phoebe grandis (Lauraceae), are probably derived biogenetically by a
Mannich-type condensation of a ketonic tetrahydroproaporphine with a
tryptamine analogue. Roemeridine is a typical example.
To this listing must be added a small but significant group of bisaporphines.
The majority of these dimers are bonded through a carbon-to-carbon linkage at
C-7 and C-7′ (e.g. Urabaine), although examples of C8-C8′ coupled
bisaporphines [e.g. (8, 8′-R)- and (8, 8′-S)-Bisisocorydine] and oxygen-bonded
dimers (e.g. 11,8′-O-Bisisocorydine, Dehatriphine) have recently been
isolated.

Cavé, A., Leboeuf, M. and Waterman, P.G. (1987) in Alkaloids: Chemical and
Biological Perspectives, (ed. S.W. Pelletier), Vol. 5, Wiley-Interscience, New York.
Gözler, B. et al. (1990) J. Nat. Prod., 53, 675 (aporphine dimers).
Guinaudeau, H. et al., Lloydia, (1975) 38, 275; J. Nat. Prod., (1979) 42, 133, 325;
(1983) 46, 761; (1984) 47, 565; (1988) 51, 389, 1025; (1994), 57, 1033
Jackman, L.M. et al. (1979) J. Nat. Prod., 42, 437.
Mix, D.B. et al. (1982) J. Nat. Prod., 45, 657 (aristolochic acids and aristolactams).
Shamma, M. and Guinaudeau, H. (1984) Tetrahedron, 40, 4795.

Morphine alkaloids (VX2900)

This extremely important group of more than 30 alkaloids is formed by phenol
oxidative coupling of a hydroxylated benzylisoquinoline precursor such as
Norlaudanosoline, itself originating from two molecules of tyrosine.
The group may be sub-divided into bases of the Salutaridine type, those
related to Morphine, which have a 4,5-oxide bridge, and those related to
Sinoacutine, which are enantiomeric with the salutaridine group.
HO MeO
HO HO
H
HO NH NMe
H
MeO
OH
O
Norlaudanosoline
Salutaridine

HO 2
1

12 10
O4 13 9
H
14
5 NMe
15 H
6 16
8
HO
Morphine
Blaskó, G. and Cordell, G.A. (1988) Heterocycles, 27, 1269.

Dibenzazecine and Hasubanan alkaloids (VX2980, VX3000)

These two groups may appear at first sight to belong to quite different structural
groups, but there is little doubt that biosynthetically they are not too disparate,
as is evidenced by their occurrence in the same plant, Stephania japonica. Both
groups are derived from two tyrosine units, but their biosynthesis is not simple.
A central, pivotal intermediate appears to be a hydroxylated benzylisoquinoline
which can cyclise, by alternative phenol oxidative coupling processes, to a
hydroxysalutaridine, or isomer. This biosynthetic route is exceptional since it
would appear that two hydroxy-groups need to be present in one of the aromatic
rings; in all other known cases of oxidative coupling, only one hydroxy-group
seems to be essential. The biosynthesis obviously has affinities with that of the

171
morphine alkaloids, although there is clearly an important divergence in the
later stages.
Tyrosine

OH OH
MeO MeO MeO
HO

NR NR NR
MeO OH MeO OH MeO OH
OH
O O

OMe
MeO 2
3 4 MeO 3
2 1
1 6 4 11
5 MeO 10
12
NMe 16
13 9
9 14
13
8 5 NMe
12 10 6 8
MeO 11 OMe O
7 OMe
OMe
Protostephanine
Hasubanonine

Protoberberine alkaloids (VX3100, VX3240)

These tetracyclic alkaloids are derived from benzylisoquinolines by
condensation with a one-carbon unit (the berberine bridge). This group of
alkaloids consists of:
(a) the simple tetrahydroprotoberberines, e.g. Tetrahydropalmatine:

MeO 4 5
6

MeO 1 N
8
H 13
OMe
12
11 OMe
Tetrahydropalmatine

(b) the protoberberines, such as Berberine;

(c) 13-methyl derivatives, such as Corydaline;
(d) miscellaneous bases, e.g. Orientalidine, which has an extra carbon atom
at C-12.
(e) ring-opened protoberberines (secoberberines) which can be regarded as
benzylisoquinolines with a carbon substituent at C-2′. The latter may occur in
different oxidation states: as an aldehyde (e.g. Aobamine), an alcohol (e.g.
Macrantaline) or as a carboxylic acid (e.g. Macrantoridine).

O NMe
MeO H CH2OH
2′ OMe

OMe
Macrantaline

172
 Structure determination in this series, i.e. the correct location of
substituents on the protoberberine ring system, has been a matter of some
difficulty and it is possible that some of the assignments currently given in DNP
will prove to be incorrect.

Narceine and phthalideisoquinoline alkaloids (VX3140, VX3200)

These alkaloids constitute further examples of oxidation products of protober-
berines, in which the nitrogen to C-8 bond has been cleaved. The narceine
group contain an ethanamine chain and, as well as relatives of narceine, include
bases which contain an enol lactone or enamine lactam function, as in Bicu-
culline imide; and those with a higher (Bicucullinine) or lower (Peshawarine)
oxidation level than Narceine.
The phthalideisoquinoline alkaloids contain an intact tetrahydroisoquinoline
ring, but oxidation of the nitrogen to C-8 bond has been followed by γ-lactone
formation; α-Hydrastine is typical of this group.
O 5 4
O NMe2
2
O
8 1 NMe
O H O O
MeO H 9

O OMe
2′ 5′ OMe
OMe 3′ 4′
OMe
Narceine
α-Hydrastine

Blasko, G. et al. (1982) J. Nat. Prod., 45, 105.

Protopine alkaloids (VX3160)

These tricyclic bases are simply formed by oxidative ring fission of proto-
berberine N-metho salts. Two of these bases (Corycavamine, Corycavidine)
have an additional methyl group at C-13.
O 4 5 O
6
+ Me
O
1 NMe O N
8
O 13 H
+ HO
O O
12
11
O O
Protopine Tetracyclic protopinium cation
Guinaudeau, H. and Shamma, M. (1982) J. Nat. Prod., 45, 237.

Rhoeadine alkaloids (VX3180)

This group of alkaloids has been encountered only in the Papaver genus. Their
biogenesis, which is not completely understood, appears to be from two tyrosine
units, via tetrahydroberberine and protopine intermediates. Oxidative fission of
the nitrogen to C-8 bond followed by oxidative cyclisation of nitrogen on to C-
15 and lactol formation results in a ring system in which C-8 becomes the lactol
carbon atom. (N.B. Other numberings of the ring system are in use; hence the
literature can be confusing.)

173
 O O 1
18 17

+
NMe
O NMe O 4
6 H
8 H 15
O
O O 12
8 11

O HO
O
O
Rhoeadine
(CA numbering)

Montgomery, C.T. et al. (1983) J. Nat. Prod., 46, 441.

Spirobenzylisoquinoline alkaloids (VX3220)

These alkaloids are derived from protoberberines by a 1,2-shift of C-8 from
nitrogen to C-14. Several mechanisms are possible, but since several of the
alkaloids contain oxygen at C-13 a route via an enolate ylid is attractive.
Closely related to this group is Lahorine, an indenobenzazepine derivative,
which may be derived biogenetically from the spirobenzylisoquinolines.

+ +
NMe NMe

–
O O

4 5
6
1 14 NMe
O 13 8

12 9

Preisner, R.M. and Shamma, M. (1980) J. Nat. Prod., 43, 305.

Benzo[c]phenanthridine alkaloids (VX3300)

This interesting group of 100 or more alkaloids is derived from
tetrahydroprotoberberine precursors by oxidation of the C-6 to nitrogen bond
followed by cyclisation of C-6 on to position 13. Various oxidation stages
exists, e.g. (a) partially reduced benzophenanthridines, as in Chelidonine; (b)
fully aromatic systems, as in Sanguinarine; (c) tricyclic alkaloids, e.g.
Corydamine; (d) tricyclic systems formed by fission of the C-6 to nitrogen
bond (benzophenanthridine numbering), e.g. Arnottianamide; (e) alkaloids
formed by addition of a carbon substituent to C-6, e.g. Corynolamine; (f)
dimeric alkaloids, e.g. Sanguidimerine.

174
 O
O
R

N
O
O
Tetrahydrocoptisine R = H
Tetrahydrocorysamine R = Me

CHO
O
R
O

NMe
O
O

HO 12
O
1
11
R 13
4 O
14
10
H
7 6 5 NMe
O
O
Chelidonine R = H
Corynoline R = Me

Several numbering systems have been used for the benzophenanthridine

alkaloids but the one shown below, based on biogenetic considerations, has been
adopted throughout DNP (this is not the numbering scheme for
Benzo[c]phenanthridine itself).

5 4
6
14 1
12 13
11
10 7
9 8 N

Krane, B.D. et al. (1984) J. Nat. Prod., 47, 1.

Phenethylisoquinoline alkaloids (VX3360)

This group arises from a phenethylisoquinoline precursor, which is itself
generated by condensation of tyrosine with a C6–C3 unit derived from
phenylalanine, probably via cinnamic acid.
In addition to the small group of simple phenethylisoquinolines, several other
of the following groups are related to them by further elaboration as shown in
Figure 18.

175
 HO
HO NMe
COOH COOH
RO +
RO NH2
OR

OH
Phenethylisoquinolines
RO 2
3 4
5 RO 12 11
1 RO 18
RO NMe NMe 10
RO 15
RO H RO 9
N 8
13 7
8 5 7
12 4 6
1110 9
3 2 1
O RO OH RO
R
Homoproaporphine Autumnaline Homoerythrina
type type type

HO
RO 3 4
5
RO 12 11 2
RO 1 10 1 H 6
2 NMe
3 16 17 RO
RO NMe RO 4 9 6a
RO
13 NMe 7
RO 14 15 H
5
R 12
8
8
11
6 7
R 10 9
MeO O RO
O R
Homomorphine type Homoaporphine type

RO RO 3 4 5
6
2
RO RO 1 7
NMe NHAc
RO RO
12 8
11
10 9
+
RO O O
RO
Colchicine type

Figure 18.

Homoaporphine alkaloids (VX3380)

E.g. Kreysigine. The sequence from tyrosine and phenylalanine via a
phenethylisoquinoline to homoproaporphines and homoaporphines appears
superficially to be exactly analogous to the course of biosynthesis of the
aporphine alkaloids. However, although Autumnaline is an efficient precursor
for both Kreysiginone and Kreysigine in Kreysigia multiflora, dienone
intermediates such as Kreysiginone are not involved in the biosynthesis of the
homoaporphines, such as Kreysigine.

Tojo, E. (1989) J. Nat. Prod., 52, 909.

Homoerythrina alkaloids (VX3440)

E.g. Schelhammeridine. These would appear to be formed by a route
analogous to that adopted in the Erythrina group.

Colchicine-like alkaloids (VX3400)

Autumnaline and O-Methylandrocymbine (but not Androcymbine itself) are
efficient precursors for Colchicine. Hence the biosynthesis must involve ring
enlargement of the dienone ring in the O-Methylandrocymbine skeleton; one
attractive suggestion is that a cyclopropane intermediate may be involved.

176
Androcymbine arises by phenol oxidative coupling, probably of Autumnaline,
by a process analogous to that involved in the biosynthesis of the morphine
alkaloids.
Lumicolchicines are the product of u.v. irradiation of Colchicine, and while
they have been reported to occur naturally, they could be regarded as artifacts.

Dibenzocycloheptylamine alkaloids (VX3410)

Dibenzocycloheptylamine alkaloids have recently been found in plants of the
genera Colchicum and Androcymbium. To date only six naturally occurring
examples are known; these include Jerusalemine and Salimine. Jerusalemine
may be formed via decarbonylation of the tropolone ring of 2-
Demethyldemecolcine by a peroxidase system present in the plant, with
accompanying oxidation. Salimine, on the other hand, may arise from
Colchicine by enzymatic peroxidation of ring C followed by hydroxylation and
methylation.

MeO
NHMe
HO
OMe

HO OMe
Jerusalemine

Erythrina and cephalotaxus alkaloids (VX2940, VX3420)

This group of alkaloids is derived from two tyrosine units by oxidative coupling
and intramolecular rearrangement and consists of about 100 alkaloids which
may be subdivided as follows:
(a) those alkaloids which contain the erythrinan skeleton (e.g. Erythraline);
these constitute the majority;
(b) those alkaloids in which the aromatic ring of erythraline has been replaced
by an unsaturated lactone ring, e.g. β-Erythroidine;
(c) the cephalotaxine alkaloids, in which the hydroaromatic component has
undergone a skeletal rearrangement. Some of these alkaloids occur as half-esters
with dihydroxydicarboxylic acids (e.g. Harringtonine);
(d) a small group of alkaloids, known as homoerythrina alkaloids, contain an
additional carbon atom in the skeleton. Such alkaloids, e.g. Schelhammeridine,
occur in the genera Schelhammera and Cephalotaxus;
(e) an even smaller group of alkaloids which contain an additional nitrogen
atom in ring D. These 16-azaerythrinanes, e.g. Erymelanthine, are possibly
derived biogenetically by in vivo oxidation of the aromatic ring of compounds
possessing the classical erythrinan skeleton followed by uptake of ammonia and
recyclization;
(f) a few so-called dimeric alkaloids that incorporate a tryptophan moiety, e.g.
Erysopinophorine.

177
 HO HO
MeO HN MeO N

MeO
MeO O
OH
Erysodienone

O 12
16
15 9
O N 5 N
13
6 7

3 1 H
2
MeO
Erythraline Erythrinan, 9CI

Amer, M.E. et al. (1991) J. Nat. Prod., 54, 329.

Findlay, J.A. (1976) Cephalotaxus Alkaloids, in MTP Series 2, Vol. 9, Alkaloids (ed. K.
Wiesner), Butterworths, London.
Hudicky, T. (1987) in Alkaloids: Chemical and Biological Perspectives, (ed. S.W.
Pelletier) Vol. 5, Wiley-Interscience, New York.
Mondon, A. (1970) Erythrina Alkaloids, in Chemistry of the Alkaloids, (ed. S.W.
Pelletier), Van Nostrand Reinhold, New York.

Amaryllidaceae alkaloids (VX3500)

This group of alkaloids is also derived from two tyrosine units which combine,
with loss of one carbon atom, to give a benzylphenylethylamine precursor unit,
e.g. Norbelladine, which by various oxidative cyclisation processes, prominent
among which are phenol oxidative coupling reactions, can give rise to the nine
major skeletal groups.
COOH

HO NH2
6
5 OH
H 1 2
9 8 N 7 OH
6′
5′ 1′
2′
HO 3′

Norbelladine
MeO

MeO NMe
H

O
O
Cryptostyline I

(a) Cryptostyline I, cherylline, and nivalidine.

Oxidation of a norbelladine-type precursor at C-7 followed by cyclisation at C-
2′ gives the simple 1-phenyltetrahydroisoquinolines exemplified by
Cryptostyline I, whereas oxidation at the alternative benzylic position (C-9) and
cyclisation at C-6 gives the 4-phenyltetrahydroisoquinolines related to
Cherylline. Oxidative coupling of positions 2 and 2′ gives the skeleton of
Nivalidine, but this may be an artifact, derived from Galanthamine.

(b) Galanthamine, haemanthidine, tazettine, and pancracine groups.

Oxidative coupling of C-2 with C-1′ in Norbelladine gives the Galanthamine
skeleton which, by an obvious cyclisation process (nitrogen to position 1), can
give rise to the Haemanthidine ring system. Opening of the carbinolamine

178
function in Haemanthidine followed by a redox reaction and cyclisation of the
oxygen at C-6 on to position 11 (Haemanthidine numbering) then affords the
Tazettine skeleton.
A further possibility is the migration of C-18 in the haemanthidine skeleton to
position 11, which gives rise to the ring system present in Pancracine and
Montanine.

6
5 OH
H 1 2 5 4 OH
9 8 N 7 OH O 12
6′
1′ 12a 2
2′
HO MeO 6 12b 1
11
8
9
N
Me
Galanthamine (9CI)
16
OMe
2
4 MeO
1 H 17 1 11
12b N Me 4 OH
O 12
6 5 O 10
19 13
15 12a 17 18
OH H 12
13 7 15 14 5
O
9 8 O O 7 6 N

Tazettine OH
Haemanthidine

OH
OH

O OH
H
O NH
O
Narciclasine

(c) Lycorine and Lycorenine alkaloids

A double cyclisation of C-2 to C-3′ and nitrogen to C-2′ provides the tetracyclic
skeleton characteristic of Lycorine and its analogues. Further modification of
this ring system by oxidative fission of the nitrogen to C-7 bond followed by
attachment of oxygen at C-7 to position 1 (galanthan numbering) then gives rise
to Lycorenine.

HO 3′
1′
6′ 9 8 7
N 1
2 OH
H 6
OH

3
OH
HO MeN H 12
1 3 17 4
15 H 12 16 5
O 11 MeO 11
13
14 16 4 15
H 6 5 14
H6
13
O
8 7 N MeO 8 7 O

OH OH
Lycorine Lycorenine
(Galanthan group, 9CI)

179
(d) Narciclasine alkaloids
This small group, exemplified by Narciclasine, also stems from Norbelladine,
and appears to be formed via Crinine (but not 3-Epicrinine) by loss of the two
carbon bridge and appropriate oxidations.
It should be noted that several of the Amaryllidaceae alkaloids occur in
enantiomeric forms.

Ghosal, S. et al. (1985) Phytochemistry, 24, 2141.

Jeffs, P.W. (1973) in MTP Series One, Vol. 9, Alkaloids (ed. K. Wiesner), Butterworths,
London.

Mesembrenoid alkaloids (VX3600)

Derived from two phenylalanine units with loss of one of the ethanamine side-
chains, this group of about 20 alkaloids is typified by Mesembrine; a second
sub-group contains alkaloids in which the pyrrolidine ring has not been formed,
as in Joubertiamine. A third variant contains bases in which a pyridine ring has
been fused on, as in Tortuosamine.

OMe
OMe
2′

3 4
5
2
1 6
N 7
O
Me H
Mesembrine

Emetine group alkaloids (VX3690)

The emetine group of alkaloids are unique among the isoquinoline group in that
they are also derived from a monoterpenoid unit via Secologanin. Incorporation
of one phenylalanine/tyrosine unit gives the alkaloids exemplified by Ipecoside
and Protoemetine; the latter, by combination with a second amino acid unit,
gives rise to the Emetine group. Alternatively, combination with a tryptamine
unit gives the typical alkaloids of Alangium lamarckii, e.g. Alangimarckine.

HO COOH
HO
NH2 HO NAc

OHC H H
H OGlc
OGlc
H
H O
O MeOOC
MeOOC
Ipecoside
Secologanin

MeO 8 7 MeO
6
5 N
MeO 11 11b N MeO
H H
1 3
2
H H
α
H
CHO
HN2′ 1′ 8′ OMe
Protoemetine
5′ 5′ OMe
Emetine

Openshaw, H.T. (1970) in Chemistry of the Alkaloids, (ed. S.W. Pelletier), Van Nostrand
Reinhold, New York.
Wiegrebe, W. et al. (1984) J. Nat. Prod., 47, 397.

180
Phenanthroindolizidine and phenanthroquinolizidine alkaloids
(VX3700, VX3760)
These alkaloids are derived from two molecules of phenylalanine or tyrosine,
together with, presumably, ornithine (→ Tylophorine group) or lysine (→
Cryptopleurine group).
OMe OMe
MeO 2 1 MeO
3
4 H
14 13

9 N 11 N
5
6
7 8
MeO MeO
OMe
Tylophorine Cryptopleurine

Alkaloids derived from tryptophan

The group of alkaloids derived from tryptophan constitutes the largest, most
varied and most fascinating of all alkaloid groups. The alkaloids include simple
tryptamine derivatives, carbazoles (in which the ethanamine chain has been
lost), a variety of alkaloids in which tryptamine has combined with one or more
prenyl residues, and others in which regular monoterpenoid or diterpenoid units
have been incorporated. However, the largest group, and the most extensively
studied, is the alkaloids derived from tryptophan and a monoterpenoid unit
based on Secologanin.

Simple tryptamine alkaloids (VX4000, VX4040, VX4140, VX4160)

The simplest indole alkaloid is Gramine. A number of simple tryptamine
derivatives also occur naturally. Other relatively simple derivatives include the
constituents of the Calabar bean, e.g. Physostigmine, several dimers, e.g.
Chimonanthine, and several oligomers, e.g. Hodgkinsine (a trimeric species),
the Quadrigemines, which are tetramers, and even a pentamer, Psychotridine.
Me H
N N
NMe2

N
H
N N
Gramine H Me
Chimonanthine

Physostigmine-like alkaloids (VX4100)

Physostigmine, the prototype of this group of alkaloids, was first isolated from
Physostigma venenosum and has also been produced by Streptomyces spp. The
alkaloid is characterised by a urethane group which is readily hydrolysed with
aqueous base to afford Eseroline. In addition to plant alkaloids with this
skeleton, other representatives of this class have recently been isolated from the
marine bryozoan Flustra foliacea (e.g. the Flustramines) and from skin extracts
of the Australian frog Pseudophryne coriacea (e.g. Pseudophrynamine A,
Pseudophrynaminol).

181
 MeNHCOO
8
N N
H
Me Me
Physostigmine

Carbazole alkaloids (VX4300)

All carbazole alkaloids encountered so far contain a substituent at C-3, which
seems to indicate that an isoprenoid unit, derived from mevalonate, is involved
in their biosynthesis.
This group may be sub-divided into:
(a) simple carbazoles, e.g. Glycozoline, which is simply 6-Methoxy-3-
methylcarbazole;
(b) carbazoles with an additional prenyl substituent, e.g. Ekeberginine;
(c) pyranocarbazoles, in this group a prenyl residue has cyclised on to a
phenolic hydroxy-group, as in Heptazolidine;
(d) carbazoles containing a complete monoterpene unit, e.g. Mahanimbine;
(e) bis-carbazole alkaloids, e.g. Murrafoline C.

Chakraborty, D.P. (1977) Prog. Chem. Org. Nat. Prod., Vol. 34.

Miscellaneous tryptophan derivatives

A number of derivatives of tryptophan are known in which combination with a
second amino acid affords a dioxopiperazine; introduction of one, two, or three
prenyl groups is also involved in these metabolites, almost all of which occur in
microorganisms, rather than higher plants.
O
H
HN
H
NH

N
H

Echinulin

The prototype of these mould metabolites is Echinulin, from Aspergillus

echinulatus. Others are the brevianamides, e.g. Brevianamide A, Roquefortine
(from Penicillium roquefortii), and Verruculogen (a tremorgen from P.
verruculosum), Oxaline (from P. oxalicum), and Indolactam V.

β-Carboline alkaloids (VX4240)

A large number of relatively simple β-carboline derivatives occur naturally.
These include β-carbolines unsubstituted at C-1, e.g. 1,2,3,4-Tetrahydro-6-
methoxy-2-methyl-β-carboline, those containing a methyl group at C-1, i.e. the
Harman group, and several which contain a substituent at C-1 and/or C-3. The
substituents at position 1 may be acyl, carboxyl, or they may be more complex,
as in Perlolyrine. Other bases include examples in which tryptamine has con-
densed with an isoprenoid unit, as in Borrerine, and an important group, the
canthinones, in which a 3-carbon unit attached via the indole nitrogen and C-1
results in the introduction of another ring.

182
 5 4 11 1
6 3 10 2
7 2 9 3
8 9 1 N 8 N
N N
H CH3 4
6
5
Harman O
Canthin-6-one

Another group of β-carboline derivatives have been isolated from Eudistoma

olivaceum, a Caribbean tunicate. Of these Eudistomin C, presumably derived
from tryptophan and cysteine, is typical.

N O
N
H H
MeN

Evodiamine

The alkaloids of Evodia rutaecarpa, e.g. Evodiamine, which are also derived
from anthranilic acid (q.v.), may also be included in this group.
Finally, several alkaloids from Picrasma quassioides are bis-β-carbolines, e.g.
Picrasidine M.

Aristotelia alkaloids (VX4620)

This group of metabolites is notable in that the tryptamine unit is attached to an
unrearranged monoterpenoid unit; Aristoteline is typical of the Aristotelia bases.
The hapalindoles, e.g. Hapalindole C, are a family of metabolites which have
been found in the cyanophyte, Hapalosiphon fontinalis.

H H
4 8 N
3 9 10 18
5
6 2 12 14
7 1 11 13
N H
H H
16 15

Aristoteline

Borreria alkaloids
These alkaloids also contain a regular terpenoid unit, as in Borrecapine, from
B. capitata. Borreline, from the same plant, contains a degraded monoterpene
unit. Borreverine, from B. verticillata, contains two tryptamine units and a
monoterpenoid component, and may be prepared by dimerisation of Borrerine.

Ergot alkaloids (VX4460)

These alkaloids, which occur in the fungus Claviceps purpurea, are derived
from 4-prenyltryptophan by cyclisation to give a tricyclic base related to
Chanoclavine I, which is representative of the simplest subgroup. Further
elaboration gives the tetracyclic ergoline skeleton, as in Elymoclavine, which is
present in the majority of alkaloids in this group. The most important alkaloids,
many of which have useful medical applications, are complex peptide alkaloids
formed from lysergic acid, in which C-17 in the elymoclavine-type precursor
has been oxidised to a carboxyl group, by attachment to one or more amino
acids. Ergocristine, which is based on the ergotaman nucleus, is typical.

183
 7
8 NH
9 H
10 5
4
H
12 2
13
N
H
Ergoline, 9CI

A few other metabolites, which may also be included in this group, are the
result of skeletal rearrangement. Clavicipitic acid is one such compound;
another is α-Cyclopiazonic acid. However, whereas the former is definitely a
product of prenyl-tryptophan metabolism the latter, from Penicillium cyclopium
is not, since it appears to arise from reaction of a tryptophan-acetoacetate unit
with prenyl pyrophosphate.
10′ 9′
H 11′ 8′
O N
H 12′
H
6′
HN 3′ N 5′
18
7
8 NMe
9
10 H
4

12 2
13
N
H
Ergotaman, 9CI

Floss, H.G. (1976) Tetrahedron, 32, 873.

Horwell, D.C. (1980) Tetrahedron, 36, 3123.

Monoterpenoid indole alkaloids

The extremely important and varied group of monoterpenoid indole alkaloids
originate from the condensation of tryptophan with Secologanin to give
Strictosidine, which is further elaborated to give the corynanthe alkaloids
together with an impressive array of structural variants. They can be sub-divided
into compounds of a dozen sub-groups.

Monoterpenoid-derived indole alkaloid glycosides (VX4640)

These are based on, e.g. Strictosidine and related compounds, mainly
glycosides.

Camptothecin-like alkaloids (VX4700)

These alkaloids, which also contain the quinoline ring system, are probably
derived from Strictosidine via an intermediate related, possibly, to Rubescine. In
this case conversion of the indole group into the quinoline ring involves ring
enlargement of ring B at the expense of ring C; otherwise the changes in the
formation of Camptothecin from Strictosidine are trivial.

184
 COOH

NH2 3 NH
NH N
H H H
OGlc
OHC
H H
OGlc O
MeOOC
H
O
MeOOC Strictosidine
Secologanin

9 7
10 6
11 2
N O N O
N N
H H H
H
20 O
O
OH
O OGlc
Camptothecin Rubescine

Hutchinson, C.R. (1981) Tetrahedron, 37, 1047.

Indoloquinolizidine alkaloids (VX4780)

These are alkaloids in which a Strictosidine precursor has been elaborated with
formation of a pyridine ring, as in Angustine.
The biogenesis of some of these alkaloids is not readily apparent. Since in
many cases these indolopyridines occur together with related glycosidic
alkaloids whose aglycones can react with ammonia to give precursors for the
pyridine ring, it may be that many of these pyridinoid bases are artifacts.
Corynantheine types which have lost one or more of the carbon atoms 16–19,
e.g. Deplancheine, are also part of this group.

Kisakurek, M.V., Leeuwenberg, A.J.M. and Hesse, M. (1983) in Alkaloids: Chemical

and Biological Perspectives, (ed. S.W. Pelletier) Vol. 1, Wiley-Interscience, New
York.
Phillipson, J.D. et al. (1978) J. Nat. Prod., 41, 503.
Saxton, J.E. (ed.) (1983) The Monoterpenoid Indole Alkaloids, Wiley-Interscience, New
York.

Corynanthe alkaloids (VX4800)

This group, based on the corynan nucleus, is exemplified by Geissoschizine and
Sitsirikine.

Corynanthe tryptamine alkaloids (VX4820)

This group of about 50 alkaloids is formed from a Corynanthe moiety which is
attached via C-17 to an additional tryptamine unit, as in the Ochrolifuanines
and Usambarines.

Ajmalicine-like alkaloids (VX4860)

These are based on the oxayohimban nucleus which, in common with all other
ring systems in the indole alkaloid group, is numbered according to its
biogenetic origin.

185
 Strictosidine

9 6
10 8 7 5
11
12 1 2 4
N N
N 3 21 N
H H 14 20 H H H
15 H
19
H 18 H
16
17 MeOOC CHOMe
Corynan, 9CI Corynantheine

6
10 5
11
3 N N
N 21 N
H H 14 H H H H
13
19
H 16
H
17 O O
MeOOC
Oxayohimban, 9CI Ajmalicine

Oxindole alkaloids (VX4940)

These are analogues of Corynantheine, e.g. Rhynchophylline, which are based
on the corynoxan nucleus, or oxindole analogues of ajmalicinoid alkaloids, e.g.
Formosanine, which are based on the formosanan nucleus.
5 5
7 H 7 H
10 N 10 N
11 2 3 21 11 2 3 21
14 H 18 14 H
N N
H 19 H 19
H 16
H 16
O
17

Corynoxan, 9CI Formosanan, 9CI

In all the former four groups of alkaloids, stereoisomerism at positions 3, 19,

and 20 is common, but C-15 has the unique configuration shown. This
stereochemical constancy at C-15 is observed in virtually all known indole
alkaloids.

Gelsemium alkaloids (VX5000)

These alkaloids contain an oxindole function and a cage-like, hydroaromatic
residue which can be imagined, in a formal sense, to arise from an intermediate
related to anhydrovobasinediol by formation of a 6,20 bond and rearrangement
to an oxindole. The major alkaloids in this group are related to Gelsemine;
however, a smaller group, characterized by Gelsedine, lack the 6,20 bond, and
have also lost C-21.
6 6
7
2 O 5NMe O NMe
N 3 21 N 20
H H
20 H

Anhydrovobasindiol

17 6 5
O 14 16
15 O NMe
3
4 3 15 21
5
9
7 6 NMe 20
12 1 2
21
N H 14
20
N O H O
H 19
18

Gelsemine

186
Yohimbinoid alkaloids (VX5040)
The Yohimbine alkaloids contain a carbocyclic ring E formed by C-17 to C-18
bond formation in a corynantheine precursor. As in the corynantheine-ajmalicine
group stereoisomerism at all asymmetric centres except C-15 is known.
6
10 5
11 2
1 N4
N 3 21
H 14 H
H 15
20
H 18
17

Yohimban, 9CI

Structural variations include the presence of methoxy-groups in the aromatic

ring, hydroxy- or acyloxy-groups at C-18, as in Reserpine, and various degrees
of unsaturation in rings C-E, as in Alstoniline.

Akuammiline alkaloids (VX5200)

The ring system in this group is formed from a precursor of the corynantheine
type by bond formation between C-16 and C-7. In addition to close relatives of
Akuammiline, variations in this subgroup include alkaloids derived by C-3 to
N-4 bond fission and C-2 to N-4 bonding, e.g. Echitamine; alkaloids with the
Echitamine skeleton in which the C-21 to N-4 bond has been broken, e.g.
Eripine; alkaloids in which the N-4 to C-5 bond in the Akuammiline skeleton
has been severed, e.g. Aspidodasycarpine; a small group of alkaloids derived
by fission of the C-21 to N-4 bond, as in Macroline. Most of the alkaloids have
a bond between the oxygen at C-17 and C-21, as in Alstophylline; and finally
Nareline, a hitherto unique alkaloid with the aspidodasycarpine carbon
skeleton, and an additional bond between C-21 and C-6.
H 16 17
17
6
5
H CH2OH
9 6
2 16
1 3 N
N 15 21 12 NMe 21
H 20
N
3
14 14
Me 20
H H
18 18 O
Akuammilan, 9CI Macroline

Sarpagine alkaloids (VX5100)

The Sarpagine (Akuammidine) group, based on the sarpagan nucleus, arises
from bond formation between C-16 and C-5 of the corynantheine precursor and
consists of simple Akuammidine derivatives; compounds in which the C-3 to N-
4 bond has been severed, e.g. Vobasine; derivatives of the oxindole obtained
following migration of C-3 from C-2 to C-7, e.g. Gardneramine; and a small
group of miscellaneous bases, in which extensive rearrangement appears to have
occurred. These may be exemplified by Ervatamine, Ervitsine, and Koumine.
Inclusion of Ervatamine in this group receives support from the conversion of a
dihydrovobasine (Tabernaemontanine) into Ervatamine in vitro.
MeOOC CH2OH H CH3
6 6
7 10 7
16 5 16 5
2 11 2
3 N
4
1 3 N
4
N 15 21 N 15 21
H H 20 H H 20
14 14
19

18 18

Akuammidine Sarpagan, 9CI

187
 COOMe
6 5
16 NMe
15
20
N 3 14
H H
19
O
Ervatamine

Ajmaline alkaloids (VX5120)

The ajmaline group contains both 5, 16 and 7, 17 bonds. Ajmaline itself is the
best known example. Almost all the bases in this group contain the same
skeleton, but Perakine and Raucaffrinoline afford a rare structural variation in
which the 21, N bond has been replaced by a 19, N bond.
6
9 16
10 8 7 5
11 2 17
12
13
1 3 N4 21
N 15 19
H 20
14 18
Me
Ajmalan, 9CI

Kingston, D.G.I. and Ekundago, D. (1981) J. Nat. Prod., 44, 509.

Pleiocarpamine alkaloids (VX5220)

In this group a corynantheine precursor has cyclised via C-16 on to N-1, as in
Pleiocarpamine.

Cinchona alkaloids (VX5240)

This important and well-known group, which includes the valuable antimalarial
quinine, consists of two sub-groups:
(a) the Cinchonamine group, derived from a corynantheine-type precursor by
fission of the N-4 to C-5 bond, and attachment of N-4 to C-17;
(b) the Quinine group, which contain a quinoline ring system generated from
a precursor of the cinchonamine type by 2, 7 bond fission followed by bonding
of N-1 to C-5.
H
6 OH
7 5
2 4
HO
1 3 N H N
N
H H 17 H
MeO

H N
Cinchonamine Quinine

Uskokovic, M.R. and Grethe, G. (1976) in MTP Series 2, Vol. 9, Alkaloids, (ed. K.
Wiesner), Butterworth, London.

Strychnos alkaloids (VX5280)

The Strychnos alkaloids are mainly based on the curan and strychnidine
skeletons. The biogenesis presumably involves migration of C-3 in a corynanthe
precursor from C-2 to C-7 followed by formation of the 2,16 bond. An early

188
 6 5
H
N
21
9 14
2 15 20 H
12 1 16
N 19
H H 17 H
H 18

Curan (9CI)

H H
17 18
N Nb
1 16 3
7 15 20 10 7 14 21
2
3 8 H 14 21 11 2 15 20
4 16
N 13 aN
H H H H
10
11 12 22 23 17
22
H 19
23 18
O O
Strychnidine, 9CI
(CA numbering) (biogenetic numbering)

alkaloid in the curan group is therefore Preakuammicine, which loses

formaldehyde to give Akuammicine. Completion of the strychnidine skeleton
from the curan skeleton involves the addition of two carbon atoms, presumably
from an acetate unit.
+
Corynanthe N
precursor 3 21
N
H
MeOOC
CHO

N N

N N
H
H COOMe MeOOC CHO
Akuammicine Preakuammicine

Condylocarpan alkaloids (VX5320)

These alkaloids contain a ring system similar to that of the curan group, but are
formed by cyclisation of C-21 on to C-7 in a Corynanthe precursor, rather than
the formation of a 3,7 bond; Condylocarpine is representative. Note that loss of
the ethanamine carbons 5 and 6 gives the ring system of Uleine, which thus

+
Corynanthe 7 N
precursor 21 3
N
H
MeOOC
CHO

3
5 N 18
6 21 19
7 20 14
10 H 15
11 2
16
N H
H H
Condylofolan, 9CI
(biogenetic numbering)

189
suggests an alternative biogenetic route to the one given below. Extensive modi-
fication of this skeleton appears to have occurred in the formation of Gonio-
mine, which can be postulated to be formed by ring-opening and epoxidation of
an indolenine related to Condylocarpine followed by N-1 to C-19 bonding:

H N H N

N O O
H H2N O H

H
N

O
HN OH

Goniomine

Secodine alkaloids (VX5360, VX5380, VX4740)

This group of tricyclic alkaloids is formed by ring-opening of a precursor of the
Preakuammicine type. The alkaloids occur in various stages of reduction, and in
monomeric and dimeric forms. Andranginine, the product of an unusual
cyclisation of a dehydrosecodine, may also be included here.

N
N

N N
HOH2C COOMe H
COOMe
Secodine

N
H
N
H
MeOOC
Andranginine

Aspidosperma alkaloids (VX5400)

The skeleton of the aspidospermidine alkaloids is formed by cyclisation of a
dehydrosecodine, itself obtained from a precursor related to Preakuammicine.
The alkaloids in this very large group are mainly based on the following
structural variants:
(a) anilinoacrylate alkaloids, such as Tabersonine, which contain the
methoxycarbonyl group at C-16. The two-carbon substituent at C-20 may be a
simple ethyl group, or it may be functionalised;
(b) alkaloids lacking the C-16 methoxycarbonyl group, as in
Aspidospermine. Again, C-18 and C-19 may be an ethyl group, or C-18 may
be functionalised;

190
 8 3
10 N 7 5 N 14
11 19 6 6 21 15
7 20 18
12 21
15 5 10
16 2
H 4 20 11 2
H 17 19
3 16
N N
H H H
Aspidospermidine Aspidospermidine
(9CI numbering) (biogenetic numbering
used in DNP)

(c) alkaloids containing an ether or lactone bridge between C-18 and C-21;
(d) alkaloids containing an ether or lactone bridge between C-18 and C-15;
(e) alkaloids containing a lactone ring between C-18 and C-17, and a dihydro-
1, 4-oxazine ring between N-1 and C-12, as in Obscurinervidine:
(f) alkaloids containing an additional bond between C-18 and C-2, as in
Venalstonine;
3
5 N 14
6 H15
21
10
11 2 19
12 18
N
H 17

16
COOMe
Venalstonine
(biogenetic numbering)

(g) alkaloids containing an additional bond between C-19 and C-2, as in

Vindolinine;

N
H
20
H
2 19
N
H
H COOMe
Vindolinine

(h) the Quebrachamine group, which are derived by fission of the 7,21 bond.
These may have lost the C-16 methoxycarbonyl group (e.g. Quebrachamine)
or it may have been retained, as in Vincadine:

5
6
3
N 14
9
21 15
2 20
12 1
N 16 17
H
H COOMe
Vincadine

(i) miscellaneous alkaloids formed by a variety of other processes, e.g.

Aspidodispermine, Bannucine, Vincatine, Rhazinilam, Trichophylline,
Meloscine, Melonine and Goniomitine, which has undergone extensive
rearrangement.

Overman, L.E. and Sworin, M. (1985) in Alkaloids: Chemical and Biological

Perspectives, (ed. S.W. Pelletier), Vol. 3, Wiley-Interscience, New York.

191
Kopsane alkaloids (VX5560)
The skeleton of the kopsane group of alkaloids is simply formed by attachment
of C-22 (the methoxycarbonyl carbon) of Venalstonine to C-6, as in Kopsine.
Skeletal variations include the alternative acyloin structure, as in Fruticosine, in
which C-22 is attached to C-17.
5 3
O N H 14
6 15
9 21 20

12 1 2
16 17
N
MeOOC OH
19

18

Kopsine

Quebrachamine and pandoline alkaloids (VX5500, VX5800)

The Pandoline nucleus can be imagined to be formed by cyclisation of a
secodine derivative isomeric with that postulated as a precursor for
Aspidospermidine:
OH
21 19
N 20
N H
N H
H 17
COOMe N
H
COOMe
Pandoline

This group of alkaloids consists of:

(a) compounds containing the Pandoline (or Pseudoaspidospermidine)
nucleus:
(b) the very small Cleavamine group, more often encountered as degradation
products of other alkaloids, the nucleus of which may arise by fission of the 3,7
bond. Alternatively, and perhaps more likely, this ring system can be generated
by fission of the 16,21 bond in an Iboga skeleton (see below).

19
7 N 21
20 18
2 3 15
N 16 17 14
H
H
15,20-Dihydrocleavamine

(c) other variations in the skeleton, e.g. attachment of C-17 to C-21 (→

Pandine); enlargement of ring D, involving migration of C-21 from C-20 to C-
19 (→ Iboxyphylline); contraction of ring D, involving loss of C-21 and
attachment of C-20 to N-4 (→ Ibophyllidine).

Iboga alkaloids (VX5700)

A third mode of cyclisation of a secodine-type precursor involves formation of a
16,21 bond, which gives rise to the ring system found in Ibogamine,
Catharanthine, and numerous related alkaloids.

192
 N
COOMe
N
H

6 5
9
1 2 3 N
12
N 21 20
H 18
14
MeOOC 17
15

(–)-Coronaridine
(biogenetic numbering)

Note that the CA numbering is different.

8 7

12 19
N
13 20
18 5
N 2 4 21
H H 3 H
1

Ibogamine, 9CI
(CA numbering)

This group of alkaloids exists in both enantiomeric series which may be

defined by the chirality of C-14; thus (–)-Coronaridine is 14R, as shown above,
and (+)-Coronaridine is 14S. The best-known example of the 14S series is
probably Catharanthine.
Many alkaloids retain the methoxycarbonyl group, whereas others (e.g.
Ibogamine) have lost it. Other variations include oxidation at C-7 to give the
related hydroxyindolenines, e.g. Ibogamine hydroxyindolenine; oxidation
followed by rearrangement to the related indoxyl, e.g. Demethoxyiboluteine;
oxidative rearrangement to the corresponding oxindole, as in Tabernoxidine;
and oxidation at C-19, C-3, C-5, or C-6 with, occasionally, ether formation
between oxidised positions.

Pyridocarbazole alkaloids (VX5840)

This small, but pharmacologically important group is based on the 6H-
pyrido[4,3-b]carbazole ring system, and is exemplified by Ellipticine and
Olivacine.
Although these aromatic bases may superficially seem to be unrelated to the
mainstream indole monoterpenoid alkaloids a possible biogenesis from
Stemmadenine can be postulated, see Figure 19.

Gribble, G.W. and Saulnier, M.G. (1985) Heterocycles, 23, 1277.

Kansal, V.K. and Potier, P. (1986) Tetrahedron, 42, 2389.

Uleine-dasycarpidan alkaloids (VX5880)

This small group of alkaloids may well arise, like the Ellipticine group, from an
oxidative fission of Stemmadenine. The genesis of the three types, e.g.
Vallesamine, Uleine, and Apparicine can thus readily be explained (Figure 20).
Ngouniensine, yet another type of alkaloid that owes its origin to a
stemmadenine-type precursor, may also be included in this group. The skeleton
is so far unique in that it contains a 3,16 bond.

193
 Stemmadenine

+ OX
N
+ +
N NMe
+ +
N N N
H H H
MeOOC CH2OH MeOOC CH2
OH

H
O
18
CH3 H2C
+ +
9 19
20
21 N NMe NMe
15 14 3
12 1 2 16 +
N N N
H 17CH H H
3

Ellipticine
(biogenetic numbering)

Figure 19.

6
+ 5 N
N
Stemmadenine +
loss of C–5
N N
H H H
MeOOC CH2OH MeOOC CH2OH
Vallesamine
loss of C–6

Me H Me
+
N N
3 N
21 20
14
15
N N N
H H H H
H
Uleine
Apparicine

Figure 20.

Eburna alkaloids (VX5900)

The skeleton of these alkaloids is generated by rearrangement of the
aspidospermidine ring system, involving migration of C-21 from C-7 to C-2,
fission of the 2, 16 bond, and attachment of C-16 to N-1. This rearrangement
has been very successfully imitated in vitro.
The alkaloids consist of:
(a) Vincamine and its derivatives, which retain the methoxycarbonyl group;
(b) alkaloids such as Eburnamine and Eburnamenine, which have lost the C-
22 ester group;
(c) some derivatives in which C-18 or C-19 is oxidised, as Cuanzine;
6 6
10 7 5 10 5
11 11 H
2 21 N N
N 4 3 N 3 19
16
H 20 14 14 16 18
HO 17 15 15 17
MeOOC 19 20
22 18 21

(+)-Vincamine Eburnamenine, 9CI

(biogenetic numbering) (CA numbering)

194
 (d) The Schizozygine group, which contain an additional bond between C-2
and C-18;
(e) Andrangine and Vallesamidine, in which C-21 has simply migrated to
C-2.

Bisindole alkaloids (VX5980)

This large group of complex alkaloids consists of a wide variety of structures,
depending on the identity of the monomeric alkaloid components. Only the
major sub-groups are listed here.
(a) alkaloids derived from a corynantheine-type unit which is attached via C-
17 to another tryptamine unit, as in the Ochrolifuanines;
(b) alkaloids similar to those in sub-group (a) but in which further cyclisation
has occurred, as in the Roxburghines;
(c) alkaloids derived from a vobasine unit, which is attached via C-3 to the
aromatic ring of a second alkaloidal component, frequently an Iboga-type unit,
or a Vobasine- or Sarpagine-type unit; Conodurine and Accedinine are
examples;
(d) a clinically important group, in which a cleavamine-type unit is attached
via C-16 to the aromatic ring of an Aspidosperma unit, usually Vindoline;
Vinblastine and Vincristine are the best known examples;
(e) alkaloids derived by union of two units of the Strychnos type. Such
alkaloids, which form the major constituents of calabash curare, are composed
of two curan units linked via N-1 and C-17′, and N′-1 and C-17; C-Toxiferine
is representative. In some alkaloids additional bonds are present; for example,
C-Curarine I has an ether bridge between C-16 and C-16′, and C-Calebassine
has an additional carbon-carbon bond between C-17 and C-17′;
(f) the Vobtusine group, which is composed of two aspidospermidine-type
units linked by a spirocyclic system involving C-14 (two bonds) of one unit
with C-22′ of another unit, together with an additional carbon atom attached to
N-1′;
(g) several bases in which one component is macroline; the second
component may be derived from pleiocarpamine, sarpagine, macroline,
quebrachidine, or aspidospermidine;
(h) several bases in which one component is pleiocarpamine; the second
component may be derived from vincorine, akuammiline, aspidospermidine, or
tuboxenine; generally, the union of these two units involves two bonds;
(i) the Secamine group, which is composed of two units derived from
secodine;
(j) miscellaneous bisindole alkaloids containing one inter-unit bond;
(k) miscellaneous alkaloids containing two inter-unit bonds;
(l) a small group containing three inter-unit bonds as in Ervafoline.
(m) a small but rapidly-growing family of indolo[2,3-a]carbazole alkaloids
and the related bis-indolylmaleimides. About sixty natural products that
incorporate these ring systems are currently known. The prototype of this group
is Staurosporine, originally isolated from Streptomyces staurosporeus AM-2282
and later found to be present in several other microorganisms. Others are the
Tjipanazoles (from the blue-green alga Tolypothrix tjipanasensis) and several
metabolites from slime moulds of the genus Arcyria (e.g. the Arcyriarubins
and Arcyriaflavins).

195
 H
N
O

N N
O

4′ 5′
MeO
NHMe
Staurosporine

Gribble, G.W. and Berthel, S.J. (1993) Stud. Nat. Prod. Chem., 12, 365
(indolocarbazoles).
Lounasmaa, M. and Nemes, A. (1982) Tetrahedron, 38, 223.

Terpenoid alkaloids
(excluding those involving tyrosine or tryptophan)

Monoterpenoid alkaloids (VX6240, VX6260)

These form a small but varied class; most of them are derived from iridoid
precursors (see Terpenoid section) and may contain a pyridine or piperidine
ring. The carbon skeleton is mostly C10, but in many it is C9 and in some it is
C11. There are two major groups:
(a) those derived from iridodial-like precursors, e.g. α-Skytanthine;
(b) a diverse group derived from Secologanin, typified by Gentianine,
Bakankoside, and Gentioflavin.
CHO
H O
COOMe
H O
GlcO
N O N
Me
α-Skytanthine Secologanin Gentianine

Dendrobium alkaloids (VX6340)

These alkaloids fall biogenetically into two quite distinct groups:
(a) a group of sesquiterpene alkaloids typified by Dendrobine, from
Dendrobium nobile, with variants involving oxygenation at C-2 or C-6, and
fission of the nitrogen to C-2 bond;
H
2 3 4
11 5
MeN 10
H O H
9 7

15
16

Dendrobane, 9CI
(b) a group of indolizidine bases exemplified by Crepidamine and
Crepidine, from D. crepidatum. These are probably not terpenoid in origin, and
may be derived from shikimic acid, acetate, and ornithine.

196
Nuphar alkaloids (VX6360)
The Nuphar (water-lily) alkaloids contain a normal sesquiterpene carbon
skeleton, and can be divided into three main sub-groups:
(a) the furylpiperidine derivatives, e.g. Nuphamine;
(b) the furylquinolizidine derivatives, e.g. Deoxynupharidine;

H
1 9
2 10 8
3 7
4 N 6

O
Deoxynupharidine

(c) a group of dimeric, sulfur-containing furylquinolizidines, e.g.

Neothiobinupharidine.
O
2″
5″
H
1 9
2 S 12
3 7 15 N
4 N 6 14 13 18
23 19
22 20
H
2′
5′
O
Neothiobinupharidine, 9CI

There are also a few miscellaneous bases which are based on variants of the
above major sub-groups.

Macrocyclic sesquiterpene alkaloids (VX6320)

This group contains the ring system of dihydroagarofuran, a sesquiterpene of the
eudesmane group (see Terpenoid section), esterified with nicotinic acid or with
any of several dicarboxylic acids, e.g. Evoninic acid. Most of the alkaloids,
which occur in Euonymus and Maytenus species, among others, contain a
medium ring dilactone involving one of the dicarboxylic acids; Evonine is
typical. Some alkaloids with two dilactone medium rings have also been
isolated.

Dihydroagarofuran

Erythrophleum alkaloids (VX6460)

The alkaloids of Erythrophleum species are based on the diterpene skeleton
related to Cassaic acid. The oxidation pattern is relatively simple, involving
only C-3, C-6, C-7 and C-19. In most alkaloids C-19 is at the carboxylic acid
oxidation level. All the alkaloids are esters or amides of a C-16 carboxylic acid
with N,N-dimethylethanolamine or N-methylethanolamine. Erythrophlamine is a
typical example.
There have been some confusing structure revisions in this series.

197
 16 COOCH2CH2NMe2
COOH
15
12 H
H H
H 14
H
3 H 7
4 6 HO O
HO O H
H MeOOC
19
Cassaic acid Erythrophlamine

C19 and C20 Diterpenoid alkaloids and 4-nor analogues (VX6400,

VX6420)
The alkaloids of this group may be divided into three major structural types,
which can be further subdivided into twelve sub-groups. Although they are
obviously diterpenoid in origin few biogenetic studies have been reported, apart
from relatively early reports of the incorporation of acetate and mevalonate into
Browniine and Lycoctonine, and of mevalonate and glycine into Delcosine.
The structural types are as follows:
(a) Alkaloids based on the C19 aconitane ring system. This accounts for the
majority of the alkaloids of this group, which differ only in the pattern of
substitution by hydroxy, methoxy, acetyloxy, benzoyloxy and, occasionally,
other acyloxy groups in the ring system.
H

12 13 O
17 HH 14 16 H
1 10 9 15
2 11 H
NH 8 HN
3 5 7 H
4 6
H H
19

Aconitane, 9CI Heteratisane, 9CI

(b) A few alkaloids belong to the heteratisane group, formed from the
aconitane framework by oxidative fission of the 13,14 bond.
(c) The second major group are the C20 alkaloids, based on atidane. Few
alkaloids, as it happens, are based on the parent ring system, since many skeletal
variations are known;
13

17
12
20 16
14 20 14
9 15
1
2 10 8
NH H 7 N H
3 5
4 6 6
H H
19 18

Atidane, 9CI Hetisan, 9CI

(d) The hetisane group, in which additional rings are introduced into the
atidane ring system by formation of 14,20 and N,6 bonds.
(e) A small group of atidane 7,20 cyclic ethers, as in Ajaconine.
(f) A small group of bases in which an additional carbocyclic ring is
introduced by attachment of C-7 to C-20, as in Denudatine.
(g) Complex hetisane derivatives, e.g. Delnudine, in which further
modification of the ring system has occurred. In the case of Delnudine this has
involved the contraction of ring C.
(h) A group of dimeric atisines, exemplified by Staphisine.
(i) The third major group of alkaloids is based on the C20 veatchine skeleton,
as in Cuauchichicine.
(j) 7,20-Cycloveatchine bases, e.g. Lucidusculine.
(k) 14,20-Cycloveatchine bases, e.g. Anopterine.
(l) Miscellaneous bases.

198
Benn, M.H. and Jacyno, J.M. (1983) in Alkaloids: Chemical and Biological
Perspectives, (ed. S.W. Pelletier), Vol. 1, Wiley-Interscience.
Pelletier, S.W. and Page, S.W. (1976) in MTP Series 2, Vol. 9, Alkaloids, (ed. K.
Wiesner), Butterworths, London.
Pelletier, S.W., Mody, N.V., Joshi, B.S. and Schramm, L.C. (1984) in Pelletier, Vol. 2.
Wiesner, K. (1985) Tetrahedron, 41, 497.

Miscellaneous diterpenoid alkaloids (VX6480)

This category contains diterpenes linked by an ester function to a non-terpenoid
nitrogen-containing unit. Examples are Ryanodine and Taxine I. Also included
in this group are the indoloditerpenes. Some indole-diterpene metabolites have
lost one carbon atom from the diterpene skeleton. These include Paspalinine, a
potent tremorgen from Claviceps paspali. The penitrems, e.g. Penitrem A,
which are mycotoxins from Penicillium crustosum, are yet more complex
metabolites which have an affinity with Paspalinine but have an additional
terpene unit attached to the aromatic ring.

Miller, R.W. (1980) J. Nat. Prod., 43, 425.

Olivoretin group
These, such as Olivoretin D (Teleocidin B), are metabolites of
Streptoverticillium olivoreticuli, and show pronounced vesicant activity.
Teleocidin A1 is clearly terpenoid in origin, and so presumably are the other
teleocidins.

Daphniphylline alkaloids (VX6500)

The alkaloids of Daphniphyllum species constitute a unique group of complex
bases derived from squalene. They can be divided into six sub-groups which
differ skeletally:
(a) the Daphniphylline group;
(b) the Secodaphniphylline group;
(c) the Daphnane (9CI) group, e.g. Daphnilactone A (note that the CA
numbering differs from that most often used);
(d) the Daphnilactone B group;
(e) the Yuzurimine group;
(f) the Yuzurine group.
The secodaphniphylline group contain the carbon framework closest to that of
squalene, one carbon atom having been transferred from C-2 to C-6. Subgroups
(a) and (b) have a C30 skeleton, whereas those in (c)–(f) have lost a C8 unit, and
the Yuzurine skeleton has lost an additional carbon atom from the terminal
isopropyl group.

199
 O
23
23
O 10
21 H 21 8
7 12
17 7 8 10 17 H
2 25
H 3 1 3 2
N 13
4 N
14
16 16
6 6
15 15

Daphnane, 9CI Daphnilactone A

O
2

O O
6
OH NH

Secodaphniphylline (heavy lines trace

the precursor squalene)

Yamamura, S. and Hirata, Y. (1976) in MTP Series 2, Vol. 9, Alkaloids, (ed. K.

Wiesner), Butterworths, London.

Steroidal alkaloids
This very large group may be divided into nine subgroups. For further
information on steroid structure and biosynthesis, see the Steroid section above.

Steroidal alkaloids (pregnane type) (VX6780)

Pregnane steroids containing one or more amino groups at C-3 and/or C-20,
such as Irehdiamine A, or with an amino group at C-18 as in the
Batrachotoxins.
21
NH2
20
18
12
11 13 17
19 16
14 15
1 9
2 10 8
3 5 H
4 6 7
H2N
Irehdiamine A

Steroidal alkaloids (conanine type) (VX6700)

Alkaloids containing the conanine skeleton. Nearly all these bases contain an
amino or an oxygen function at C-3.
MeN
20
18
H

A
3

Conanine, 9CI

200
Steroidal alkaloids (spirosolane and solanidine type) (VX6660,
VX6680, VX6720, VX6740)
Alkaloids in which a cholestane side-chain has been converted into:
(a) a piperidine ring, to give the secosolanidane skeleton;
(b) a bicyclic system containing a piperidine and a tetrahydrofuran ring to
give the spirosolane skeleton;

H N H
O H N
H H

Spirosolane, 9CI Solanidane, 9CI

(c) a bicyclic system to give the solanidane skeleton;

(d) a bicyclic system in which the piperidine nitrogen has been linked to the
C-18 methyl group. This has been found only in Procevine so far, and is of
special interest because it can be regarded as a precursor of the rearranged
cevane skeleton.

H
N
H

H
HO
Procevine

(e) a pyrrolidine ring, as in Tomatillidine.

In addition, two sub-groups of alkaloids with rearranged skeletons are known.
These are;
(f) the cevane group, in which ring D in a Procevine-type precursor has been
enlarged at the expense of ring C;

N
H H H
H E H N
H
H H H
H H
H H

H Veratraman, 9CI
Cevane, 9CI

(g) the veratraman group, in which ring E of Cevane has been opened.

Steroidal alkaloids (buxus type) (VX6760)

The Buxus alkaloids are a large group of bases, the great majority of which fall
into three sub-groups:
(a) those containing the pentacyclic 4,4,14-trimethyl-9,19-cyclopregnane
skeleton. The majority of the Buxus alkaloids belong to this category.
(b) those containing a tetracyclic system in which 9,19 bond fission has
occurred to give a seven-membered ring B.
(c) those alkaloids in which one or both of the carbon atoms attached to C-4
have been lost.

201
 All the alkaloids have a nitrogen function at C-3 and/or C-20, which may be
unmethylated, partially methylated, or fully methylated.
The suffix letters used in the nomenclature of this group indicate the degree
of methylation of the nitrogen atoms:
Substitution at N-3 Substitution at N-20
——————————— ———————————
R1 R2 R3 R4
A Me Me Me Me
B Me Me Me H
C H Me Me Me
D H Me Me H
E Me Me H H
F H H Me Me
G Me H H H
H H H H Me
I H H H H
K Me Me – –
L – – Me Me
M Me H – –
N – – Me H
O H H – –
P – – H H

In DNP the entries for these alkaloids are organised under the (usually
unknown) unsubstituted parents of the I, O, or P type.

Steroidal alkaloids (salamandra type) (VX6640)

In many of these alkaloids ring A has been enlarged, with incorporation of
nitrogen, as in Samandarine.

Miscellaneous steroidal alkaloids (VX6790)

Non-nitrogenous steroids linked by an ester or acetal bond to a nitrogen-
containing unit, as in Bufotoxin.

Imidazole alkaloids (VX6920)

This group, obviously derived from histidine, consists of:
(a) the Pilocarpus alkaloids, of which Pilocarpine is typical;
(b) miscellaneous bases obviously containing a histamine moiety, e.g.
Casimiroedine;
(c) miscellaneous bases, e.g. Isolongistrobine.

Oxazole alkaloids (VX6930)

Upwards of thirty naturally occurring oxazoles are currently known. They have
been isolated from various sources – plants of the Gramineae (e.g. Annuloline)
and Rutaceae (e.g. Halfordinol), nudibranch egg masses (Ulapualides) and
microorganisms. The latter have furnished the majority of the compounds,
ranging from the simple indolyl alkaloids Pimprinine, Pimprinethine and
Pimprinaphine, to complex peptide antibiotics such as the
Mikamycin/Streptogramin/Virginiamycin family. The marine and bacterial
oxazoles appear to have been formed from peptides of aliphatic amino acids

202
while the oxazoles of the Gramineae and Rutaceae arise from the chorismic
acid-phenylalanine pathway.

Thiazole alkaloids (VX6935, VX6937)

More than 100 naturally occurring compounds that incorporate the thiazole
moiety have been isolated to date. These alkaloids are a heterogeneous group
ranging in complexity from Aeruginoic acid and the simple peptide
Herbamide A to antineoplastic cyclopeptides such as Ulicyclamide,
Ulithiacyclamide, Patellamides and Dolastatins.

Pyrazine and quinoxaline alkaloids (VX6940)

Pyrazines have been isolated from widely differing sources: from
microorganisms, plants, mushrooms, animals, insects (especially ants, where
they are considered to function as alarm pheromones) and more recently from
marine organisms, where they are the actual light emitters in bioluminescence
processes. A series of tetrahydroquinoxalines has been isolated from the scent
gland of the Canadian beaver, Castor fiber.
Pyrazines also contribute to the aroma of various foodstuffs, including coffee,
cocoa, tea and cooked meats, but from these sources they are generated by
pyrolytic processes.

Pyrrole alkaloids (VX7010)

The pyrrole alkaloids are a heterogeneous group ranging in complexity from the
very simple brominated pyrroles (e.g. 2,3-Dibromo-1H-pyrrole), simple amino
acids (Kainic acid) and peptides to the lipophylic Malyngamides, porphorins
and other tetrapyrrole pigments (see following section). Compounds that
incorporate the pyrrole moiety have been isolated primarily from marine sources
(sponges, bacteria and algae) and microorganisms.

Putrescine alkaloids (VX7020)

These alkaloids can be subdivided into
(a) simple derivatives of putrescine with one or two cinnamic acid amide
linkages, e.g. 4-Coumaroylputrescine, Feruloylputrescine (Subaphylline),
Dicaffeoylputrescine
(b) derivatives of 2-hydroxyputrescine, e.g. N-(4-Coumaroyl)- and N-
Feruloyl-2-hydroxyputrescine
(c) agmatine derivatives, e.g. 4-Coumaroylagmatine, Hordatine A
(d) miscellaneous, e.g. Aerothionin, N-Carbamoylputrescine.

Spermine and spermidine alkaloids (VX7030, VX7040,

VX7050, VX7060, VX7070)

A number of alkaloids are derived from Spermine or Spermidine, themselves

derived from ornithine via Putrescine.
H2N(CH2)3NH(CH2)4NH2 H2N(CH2)3NH(CH2)4NH(CH2)3NH2

Spermidine Spermine

203
 Condensation of either Spermidine or Spermine with one or two cinnamic acid
units, or with an unbranched carbon chain, gives the skeleton of these alkaloids.
Aside from these aliphatic amines, therefore, phenylalanine or tyrosine, and long-
chain fatty acids are involved. The biosynthesis clearly also involves phenol
coupling processes in certain cases, e.g. Codonocarpine.
The spermidine alkaloids can be subdivided into four sub-groups: (a) simple
diamides, e.g. Maytenine; (b) medium-ring compounds involving one cinnamic
acid unit in the ring, e.g. Celabenzine; (c) medium-ring compounds involving
two cinnamic acid units in the ring, e.g. Codonocarpine, Lunaridine; (d)
medium ring compounds containing a C10 to C16 unbranched carbon chain in
the ring, e.g. Cannabisativine; (e) derivatives of spermidine lengthened by one
methylene group. This small group of amides of Solamine, so-called
homospermidine alkaloids, was isolated from plants of the family Solanaceae.
Solapalmitine is representative of this class.

H3C(CH2)14CON (CH2CH2CH2CH2NMe2)2

Solapalmitine

Ph O H
N
HN
N
COPh
Celabenzine

The spermine-derived alkaloids may be divided into three sub-groups: (a) those
in which the two terminal putrescine chains form an eight-membered ring with a
cinnamic or a C8 or C10 unbranched carbon chain, e.g. Homaline; (b)
Pithecolobine in which the one large ring involves a C12 chain; (c) two alkaloids
in which two medium rings are formed with two cinnamic acid units.

Hesse, M. and Schmid, H. (1976) Macrocyclic Spermidine and Spermine Alkaloids in

MTP Series 2, Vol. 9, Alkaloids (ed. K. Wiesner), Butterworths, London.

Peptide alkaloids (VX7100)

There are now over 250 cyclopeptide alkaloids, which by definition are
composed of a number of amino acids, among which phenylalanine or tyrosine
are frequently found. Almost all of these alkaloids contain a medium ring
(13–15 membered) incorporating a β-aminostyryl component. Examples are
Frangulanine and Zizyphine A. As far as is known the component aminoacids
have the L-configuration, with a few exceptions, e.g. D-phenylserine in
Lasiodine A and D-threo-β-phenylserine and D-erythro-β-hydroxyleucine in
Scutianine E.

O O
NH
HN HN
O

NMe2
Frangulanine

204
Amanita alkaloids (VX7120)
The toxins of the European death cap mushroom Amanita phalloides and other
A. spp. constitute an even more complex group of macrocyclic peptides, mostly
containing sulphur. These include the amatoxins (e.g. α-Amanitin, β-
Amanitin), the phallotoxins (e.g. Phalloidin) and the virotoxins (e.g. Viroidin).
The fly agaric (A. muscaria) also contains the low molecular weight compound
Muscarine.

Purines (VX7300)
Purines are involved along with pyrimidines as bases in DNA and RNA. These
and other purines may be divided into;
(a) the ubiquitous, well-known oxypurines, exemplified by Caffeine;
(b) derivatives of adenine, e.g. the plant hormone, Zeatin;
(c) miscellaneous.
O
Me
N
MeN

O N N
Me
Caffeine

Pteridines and analogues (VX7350)

Pteridines are a widely distributed class of naturally occurring compounds. They
owe their exceptional position in the field of heterocyclic chemistry mainly to
their unusual chemical properties, their conspicuous fluorescence and their
importance in metabolism, and partly to their discovery as pigments in butterfly
wings. Three of the most common butterfly pigments are Leucopterin,
Xanthopterin and Isoxanthopterin. The red pigments in the eye of the fruitfly
Drosophila melanogaster, e.g. Drosopterin, Isodrosopterin and
Neodrosopterin are complex pteridine derivatives. Folic acid, a water-soluble
growth factor in bacteria and an anti-pernicious anaemia factor in animals is
also a pterin derivative with a p-aminobenzoylglutamic acid sidechain at the 6-
position. It occurs naturally as the dihydro derivative. Marine pteridines are
represented by Leucettidine and Urochordamines A and B.

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Polypyrroles (VY)
The polypyrroles (tetrapyrroles) are a numerically limited class of natural
products that are mostly strictly functional. The main examples are haems,
chlorophylls, bilins and Vitamin B12. All types of organism use tetrapyrroles of
one or more of these classes and all the functional tetrapyrroles derive from one
common tetrapyrrolic intermediate, Uroporphyrinogen III (Uro’gen III).
Uro’gen III is derived entirely from eight molecules of 5-Aminolaevulinic acid
(ALA) by the action of three enzymes, via Porphobilinogen (PBG) and
Hydroxymethylbilane (HMB) as intermediates. A particularly important feature
in Uro’gen III is the fact that ring D has been inverted and so the acetate and
propionate side-chains are not in the same order as on the other three pyrrolic
rings, A to C. This feature can be found in virtually all naturally occurring
tetrapyrroles. Some organisms, however, have a low activity of the enzyme
uro’gen III synthase (as occurs in the human disease, congenital erythropoietic
porphyria). In these cases non-enzymic cyclisation of HMB occurs to give
Uro’gen I, which has the regular alternating pattern of the acetate and
propionate side-chains, and a number of derived type I porphyrins can be
isolated from these organisms.
The main system of nomenclature used in DNP is that recommended by the
IUPAC-IUB Joint Commission on Biochemical Nomenclature. For the cyclic
tetrapyrroles this is based on the porphyrin with the carbon atoms numbered 1
to 20 and the nitrogen atoms numbered 21 to 24. This has superseded the older
‘Fischer’ numbering which numbered only the eight β-positions of the five-
membered pyrrole rings and labelled the four bridging meso-carbons α, β, γ
and δ.

3 α
2 4 5 6 7
1
2 3
21 22 8 4
1 N N 9 N N
20
H 10 δ
H β
19 H 11 H
24N N N N
18 23 12 8 5
16 14
17 15 13 7 γ 6

Porphyrin; IUPAC-IUB numbering Porphyrin; Fischer numbering

For natural porphyrins the IUPAC-IUB numbering starts on ring A and

continues to rings B, C, and D, as shown below for Uro’gen III (ring D is
always the inverted ring, see above). Chemical Abstracts on the other hand,
though it uses the same 1 to 20 numbering for the carbon atoms, starts the
numbering at such a position and in such a direction that the propionate side-
chains get the lowest possible locants (thus for Uro’gen III the numbering
would start at the position shown as 14 and proceed anticlockwise).

HOOC
COOH
COOH HOOC 5 COOH
COOH 4
HOOC
A B
1 N N
20
H H
10
H H
O N N N
NH2 NH2 H D C
14
ALA PBG HOOC 15 COOH

HOOC COOH
Uro'gen III

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 HOOC
COOH
HOOC COOH
A B
N N
H H
HO
H H
N N
D C

HOOC COOH
HOOC
COOH
HMB

Certain reduced porphyrins have recognised names: Chlorin is 2,3-

dihydroporphyrin, Bacteriochlorin is 7,8,17,18-tetrahydroporphyrin,
Isobacteriochlorin is 2,3,7,8-tetrahydroporphyrin and Porphyrinogen is
5,10,15,20,22,24-hexahydroporphyrin.

2 3 4 78 12 13 17 18
1 5
6 9 10 11 14 15 16 24 19
21 22 23
N N N N
H
Bilin; IUPAC-IUB numbering

Although several of the naturally occurring intermediates in tetrapyrrole

biosynthesis are at the porphyrinogen oxidation level (e.g. Uro’gen III), these
compounds are generally readily oxidised in air to the corresponding aromatic
porphyrins. Thus it is the porphyrins that are isolated. In addition to the
naturally occurring types I and III porphyrins (as explained above), DNP
includes other isomers for comparison purposes in many cases. For
Uroporphyrin, for example, assuming each ring has one acetate and one
propionate side-chain, there are four possible isomers or types and these are
given in the table below. In the Protoporphyrin series, however, there is a
further degree of isomerism because two of the rings have a methyl and a
propionate sidechain whereas two have a methyl and a vinyl sidechain. This
results in 15 different types, numbered by Fischer I to XV as shown in the
second table. Protoporphyrins I and II are related to Uroporphyrin I, III to V are
related to Uroporphyrin II, VI to XI are related to Uroporphyrin III and XII to
XV are related to Uroporphyrin IV. The naturally occurring Protoporphyrin is
type IX. If the Roman numeral is omitted IX is assumed.

R2 R3

R1 R4
N N
H
H
N N
R8 R5

R7 R6

Type R1 R2 R3 R4 R5 R6 R7 R8
I A P A P A P A P
II A P P A A P P A
III A P A P A P P A
IV A P P A P A A P
The substitution patterns for uroporphyrins I to IV (A = CH2COOH, P = CH2CH2COOH)

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Type R1 R2 R3 R4 R5 R6 R7 R8
I Me V Me V Me P Me P
II Me P Me V Me P Me V
III Me V V Me Me P P Me
IV Me P V Me Me V P Me
V Me P V Me Me P V Me
VI Me P Me P Me V V Me
VII Me P Me V Me P V Me
VIII Me V Me P Me P V Me
IX Me V Me V Me P P Me
X Me V Me P Me V P Me
XI Me P Me V Me V P Me
XII Me V V Me P Me Me P
XIII V Me Me V Me P P Me
XIV Me P V Me V Me Me P
XV Me P V Me P Me Me V
The substitution patterns for protoporphyrins I to XV (V = CH=CH2, P = CH2CH2COOH)

Porphyrins and porphyrinogens (VY0905)

The main biosynthetic pathway from Uro’gen III starts with the stepwise
decarboxylation of each of the four acetate side-chains to give
Coproporphyrinogen III, then oxidative decarboxylation of two of the
propionate side-chains to give Protoporphyrinogen. These porphyrinogens and
the partly decarboxylated intermediates are always isolated after aerial oxidation
to give the corresponding porphyrin which is much more stable. Enzymic
oxidation of Protoporphyrinogen gives Protoporphyrin, which is the branch
point in the pathways to the haems and bilins and to the chlorophylls. Other
porphyrins that can be found, in faeces for example, are mostly bacterial
degradation products of Protoporphyrin with modification of the vinyl groups,
e.g. Mesoporphyrin, Deuteroporphyrin and Haematoporphyrin.

Haems and metal-free haems (VY0910)

Insertion of Fe2+ into the centre of Protoporphyrin gives the uncharged Haem
(American spelling, heme), also known as Haem b or Protohaem. This is the
oxygen-carrying pigment of haemoglobin and myoglobin and the prosthetic
group of Cytochrome b. Other cytochromes have closely related haems, e.g.
haems a, c, d, and o. The Fe3+ form is called Haemin; it is positively charged
and requires a counterion, as in Haemin chloride. Haematin is specifically the
hydroxide salt. Many other metals can be inserted into porphyrins synthetically
but apart. from magnesium (see Chlorophylls), zinc is the only metal that is
sometimes found naturally as a result of disorders in iron metabolism.

Bile pigments (bilins) (VY0915)

In animals the degradative pathway for haem is via an oxidative ring cleavage
to give Biliverdin (Biliverdin IXα). This is then reduced to Bilirubin (10,23-
dihydrobiliverdin) and excreted, as a bis-glucuronide ester, through the bile duct
into the gut, where further reduction of double bonds by bacteria occurs. The
same oxidative cleavage of haem can be effected non-enzymically by the
coupled action of oxygen and a reducing agent such as ascorbic acid. In this
reaction, cleavage can occur at any one of the four meso positions (C-5, 10, 15
and 20) and thus four isomeric Biliverdins (IXα, β, γ and δ) are produced.

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 In plants the same oxidative cleavage of haem leads to the photoresponsive
pigment Phytochromobilin and, in algae, to the light-harvesting pigments such
as Phycocyanobilin. Both of these are found in vivo covalently attached to
proteins by thioether links.

Chlorophylls and derivatives (VY0920)

Insertion of Mg2+ instead of Fe2+ into protoporphyrin is the start of the pathway
that leads to the chlorophylls. A key intermediate in this pathway is Proto-
chlorophyllide, in which the carbocyclic ring E, found in all chlorophylls and
bacteriochlorophylls, has been formed in an oxidative cyclisation reaction. The
chlorophyll c family, found in phytoplankton, have a porphyrin skeleton derived
from Protochlorophyllide by insertion of a double bond into the propionate side-
chain but the plant chlorophylls are all chlorins, having the C-17/18 double
bond reduced in a photochemical, NADPH-dependent reduction of
Protochlorophyllide giving Chlorophyllide a. Esterification with phytol gives
Chlorophyll a; Chlorophyll b has, in addition, the 7-methyl oxidised to a
formyl group.
There are a number of compounds in DNP which are the result of chemical
degradation of chlorophylls and were used in the classical proof of its structure.
For example Phaeophytin a is the magnesium-free derivative and
Phaeophorbide has, in addition, the phytyl ester hydrolysed. Under more
vigorous conditions further degradation occurs, especially of the sensitive β-
ketoester functionality in ring E.

Bacteriochlorophylls and derivatives (VY0925)

Photosynthetic bacteria rely on a slightly more diverse range of tetrapyrrole
pigments. Purple photosynthetic bacteria contain Bacteriochlorophyll a, which
is a bacteriochlorin, having two opposite pyrrole rings reduced. Green sulfur
bacteria on the other hand contain Bacteriochlorophylls c, d and e, which are
in fact chlorins not bacteriochlorins and are each a family of pigments with
varying numbers of extra methyl groups introduced onto the C-8 and C-12 side-
chains. Other less common pigments have been named Bacteriochlorophyll b
and g but Bacteriochlorophyll f, proposed to be the 20-desmethyl derivative of
Bacteriochlorophyll e, has not yet been discovered.
Bacteriochlorophylls also have a wider range of esterifying groups than do
the chlorophylls. Thus, whereas Bacteriochlorophyll a usually has the normal
phytyl ester, Bacteriochlorophylls c, d and e commonly have a farnesyl group.
Geranylgeranyl and straight-chain hydrocarbon esters are also found in some
organisms.

Vitamin B12, precursors and variants (VY0930, VY0935)

Another pathway of tetrapyrrole biosynthesis, found in bacteria, leads to
Vitamin B12 and related compounds. Methylation of the macrocycle gives
Precorrin 2, which is also thought to be the precursor of Sirohaem (prosthetic
group of sulfite and nitrite reductases), Factor F430 (cofactor involved in
methanogenesis) and Haem d1, (prosthetic group of Cytochrome cd1, a
dissimilatory nitrite reductase). Further intermediates on the route to Vitamin
B12 are Precorrin 6x and either Hydrogenobyrinic acid or its cobalt derivative
Cobyrinic acid.
Vitamin B12 can exist with the cobalt in oxidation state (I), (II) or (III),
though (III) is the most stable. In this oxidation state the metal requires an upper
axial ligand (the nucleotide loop provides the lower ligand). The normal

209
isolation procedure introduces a cyanide ligand (Cyanocobalamin) but water,
hydroxide, or nitrite are other possibilities. The two biologically active forms of
Vitamin B12 both have Co-C bonds: Coenzyme B12 has an axial adenosyl group
and is the cofactor for a number of enzymic rearrangement reactions and
Methylcobalamin has a methyl as the axial group and is involved in enzymic
methyl-transfer reactions.
A number of close relatives of vitamin B12 have been found in various
anaerobic bacteria. These have the dimethylbenzimidazoyl group of the
nucleotide loop replaced by other substituted benzimidazoyl groups or by
purines or even by simple phenoxy groups. The latter type of group cannot
provide the lower ligand to the cobalt ion.

Geoporphyrins (VY0940)
A wide range of tetrapyrrole derivatives have been found in sedimentary
deposits derived from organic matter, such as crude oil, oil shales and lignite.
These porphyrins have undergone various degradative reactions: generally the
macrocycle is at the stable porphyrin oxidation level but the side chains are
fully reduced and very often decarboxylated; they very often occur as nickel or
vanadyl complexes. Thus one of the most common geoporphyrins is
Deoxophylloerythroetioporporphyrin (DPEP), which could well be derived
from degradation of Chlorophyll a. The arrangement of the substituents on the
geoporphyrins gives a clue to their origin and thus the type of organic material
which gave rise to the deposit. For example, geoporphyrins that lack a
substituent at C-7 are assumed to derive from Chlorophyll b or related
compounds, whereas those in which a cyclisation onto the C-17 side-chain has
occurred (such as examples with a methylated five-membered ring) may derive
from the Chlorophyll c family. Other geoporphyrins have been isolated which
have the additional carbon atoms on the C-8 and C-12 side-chains characteristic
of Bacteriochlorophylls c, d and e. The types of reaction undergone by the
porphyrins also give useful information about the conditions that they have
experienced over the history of the deposit.

Miscellaneous polypyrroles (VY0945)

Although the majority of tetrapyrroles found in organisms are the ones
described above, widely-distributed and having specific well understood
catalytic functions, there are a few that are found in individual organisms and
have more obscure or unusual functions. Some are present purely as pigments,
for example in certain birds’ eggs and butterfly wings. Among the unusual
functions are those of Bonellin, produced as a hormone by the females of a
certain marine worm to ensure her offspring remain male, and Substance F,
which is responsible for the bioluminescence of krill. Other examples, such as
Corallistin A from a sponge or Chlorophyllone a from a type of clam, do not
have any recognised function.

Blanche F. et al. (1995) Angew. Chem., Int. Ed. Engl., 34, 383 (biosynth).
Dolphin, D. (ed.) (1978–79) The Porphyrins, Vols 1–7, Academic Press, New York.
Dolphin, D. (ed.) (1982) B12, Vols 1–2, Wiley, New York.
Jordan, P.M. (ed.) (1991) Biosynthesis of Tetrapyrroles, Elsevier, Amsterdam.
Leeper, F.J. (1985) Nat. Prod. Rep., 2, 19, 561; (1987) 4, 441; (1989) 6, 171 (biosynth).
Scheer, H. (ed.) (1991) Chlorophylls, CRC Press, Boca Raton.
Smith, K.M. (ed.) (1975) Porphyrins and Metalloporphyrins, Elsevier, Amsterdam.
Zagalak, B. and Friedrich, W. (eds) (1979) Vitamin B12, de Gruyter, Berlin.
The Biosynthesis of the Tetrapyrrole Pigments (1994) Ciba Foundation Symposium ,
180, Wiley, Chichester.

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